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Committee 8

Pharmacological Treatment ofUrinary Incontinence

Chairman

KARL-ERIK ANDERSSON (USA)

Co-Chairman

C. R CHAPPLE (U.K)

Members

L. CARDOZO (U.K),

F. CRUZ (Portugal),

H. HASHIM (U.K),

M.C. MICHEL (The Netherlands),

C. TANNENBAUM (Canada),

A.J. WEIN (USA)

632

REFERENCES

III. DESMOPRESSIN

II. OTHER STEROID HORMONERECEPTOR LIGANDS

I. ESTROGENS

E. HORMONAL TREATMENT OFURINARY INCONTINENCE

D. DRUGS USED FORTREATMENT OF

OVERFLOW INCONTINENCE

IV. SEROTONIN-NORADRENALINEUPTAKE INHIBITORS

III. ββ-ADRENOCEPTOR AGONISTS

II. ββ-ADRENOCEPTOR ANTAGONISTS

I. αα-ADRENCEPTOR AGONISTS

C. DRUGS USED FORTREATMENT OF STRESSURINARY INCONTINENCE

XII. FUTURE POSSIBILITIES

XI. COMBINATIONS

X. OTHER DRUGS

VII. ANTIDEPRESSANTS

VI. PHOSPHODIESTERASE (PDE)INHIBITORS

V. ββ-ADRENOCEPTOR AGONISTS

IV. αα-ADRENOCEPTOR (AR)ANTAGONISTS

III. DRUGS WITH “MIXED” ACTION

II. DRUGS ACTING ON MEMBRANECHANNELS

I. ANTIMUSCARINIC(ANTICHOLINERGIC) DRUGS

B. DRUGS USED FORTREATMENT OF OVERACTIVE

BLADDER SYMPTOMS/DETRUSOR OVERACTIVITY

VI. MUSCARINIC RECEPTORS

V. BLADDER CONTRACTION

IV. PATHOGENESIS OF BLADDERCONTROL DISORDERS

III.PERIPHERAL NERVOUS CONTROL

II. CENTRAL NERVOUS CONTROL

I. PUBLICATION SEARCHES

A. INTRODUCTION

CONTENTS

IX. TOXINS

VIII. CYCLOOXYGENASE (COX) INHIBITORS F. CONSIDERATIONS IN THEELDERLY

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The function of the lower urinary tract (LUT) is to storeand periodically release urine, and is dependent onthe activity of smooth and striated muscles in thebladder, urethra, and pelvic floor. The bladder andthe urethra constitute a functional unit, which iscontrolled by a complex interplay between the centraland peripheral nervous systems and local regulatoryfactors [Andersson, 1993; de Groat and Yoshimura,2001; Andersson and Wein, 2004]. Malfunction atvarious levels may result in bladder control disorders,which roughly can be classified as disturbances offilling/storage or disturbances of voiding/emptying.Failure to store urine may lead to various forms ofincontinence (mainly urgency and stress incontinence),and failure to empty can lead to urinary retention,which may result in overflow incontinence. A disturbedfilling/storage function can, at least theoretically, beimproved by agents decreasing detrusor activity,increasing bladder capacity, and/or increasing outletresistance [Wein, 2007].

Many drugs have been tried, but the results are oftendisappointing, partly due to poor treatment efficacyand/or side effects. The development of pharmacologictreatment of the different forms of urinary incontinencehas been slow, but several promising targets anddrug principles have been identified [Andersson etal., 2002; 2005; Andersson, 2007; Colli et al., 2007].

In this report, we update the recommendations fromthe 2004 International Consensus meeting [Anderssonet al., 2005]. The most relevant information obtainedsince the last meeting is reviewed and summarised.Agents specifically used for treatment of urinary tractinfections and interstitial cystitis, have not beenincluded. Our clinical drug recommendations arebased on evaluations made using a modification of theOxford system (Table 1). The terminology used isthat recommended by the International ContinenceSociety (ICS) [Abrams et al., 2002].

The review undertook a comprehensive search of allmajor literature databases and the abstract booksfrom several major conferences: American UrologicalAssociation, ICS, European Association of Urology,International Urogynaecological Association,International Consultation of Incontinence and SocieteInternationale d’Urologie. There were no restrictionson the inclusion of publications by language;publications in languages other than English weretranslated into English.

I. PUBLICATION SEARCHES

A. INTRODUCTION

Pharmacological Treatment ofUrinary Incontinence

KARL-ERIK ANDERSSON

C. R CHAPPLE, L. CARDOZO, F. CRUZ, H. HASHIM, M.C. MICHEL, C. TANNENBAUM, A.J. WEIN

Table 1. ICI assessments 2008: Oxford guidelines(modified)

Levels of evidence

Level 1: Systematic reviews, meta-analyses, good quality randomized controlled clinical trials (RCTs)

Level 2: RCTs , good quality prospective cohort studies

Level 3: Case-control studies, case series

Level 4: Expert opinion

Grades of recommendation

Grade A: Based on level 1 evidence (highly recommended)

Grade B: Consistent level 2 or 3 evidence (recommended)

Grade C: Level 4 studies or ”majority evidence” (optional)

Grade D: Evidence inconsistent/inconclusive (no recommendation possible) or the evidence indicates that the drug should not be recommended

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In the adult individual, the normal micturition reflex ismediated by a spinobulbospinal pathway, whichpasses through relay centers in the brain (Figure 1).In infants, the central pathways seem to be organizedas on-off switching circuits, but after the age of fourto six years, voiding is initiated voluntarily by thecerebral cortex [de Groat et al., 1999]. Studies inhumans and animals have identified areas in thebrainstem and diencephalon that are specificallyimplicated in micturition control, including Barrington’snucleus or the pontine micturition center (PMC) inthe dorsomedial pontine tegmentum [Griffiths, 2004.,Fowler et al., 2008]. These structures directly excitebladder motoneurons and indirectly inhibit urethralsphincter motoneurons via inhibitory interneurons inthe medial sacral cord. The periaqueductal grey (PAG)receives bladder filling information, and the pre-opticarea of the hypothalamus is probably involved in theinitiation of micturition. According to PET-scan andfunctional imaging studies in humans, thesesupraspinal regions are active during micturition[Griffiths, 2004; Blok et al., 1998; Nour et al., 2000;Athwal et al., 2001; Griffiths et al., 2007; Hruz et al.,2008; Mehnert et al., 2008; Tadic et al., 2008].

Bladder emptying and urine storage involve a complexpattern of efferent and afferent signalling inparasympathetic, sympathetic, somatic, and sensorynerves (Figures 2-4). These nerves are parts of reflexpathways, which either keep the bladder in a relaxedstate, enabling urine storage at low intravesicalpressure, or which initiate micturition by relaxing theoutflow region and contracting the bladder smoothmuscle. Contraction of the detrusor smooth muscleand relaxation of the outflow region result from

activation of parasympathetic neurones located in thesacral parasympathetic nucleus (SPN) in the spinalcord at the level of S2-S4 [de Groat et al., 1993]. Thepostganglionic neurones in the pelvic nerve mediatethe excitatory input to the human detrusor smoothmuscle by releasing acetylcholine (ACh) acting onmuscarinic receptors. However, an atropine-resistantcomponent has been demonstrated, particularly infunctionally and morphologically altered human bladdertissue (see below). The pelvic nerve also conveysparasympathetic fibres to the outflow region and theurethra. These fibres exert an inhibitory effect andthereby relax the outflow region. This is mediatedpartly by release of nitric oxide [Andersson andPersson, 1993], although other transmitters might beinvolved [Bridgewater and Brading, 1993; Hashimotoet al., 1993; Werkström et al., 1995].

Most of the sympathetic innervation of the bladderand urethra originates from the intermediolateral nucleiin the thoraco-lumbar region (T10-L2) of the spinalcord. The axons travel either through the inferiormesenteric ganglia and the hypogastric nerve, or passthrough the paravertebral chain and enter the pelvicnerve. Thus, sympathetic signals are conveyed inboth the hypogastric and pelvic nerves [Lincoln andBurnstock, 1993].

The predominant effects of the sympathetic innervationof the lower urinary tract are inhibition of theparasympathetic pathways at spinal and ganglionlevels (demonstrated in animals), and mediation ofcontraction of the bladder base and the urethra (shownin animals and man, see Andersson, 1993). However,the adrenergic innervation of the bladder body isbelieved to inactivate the contractile mechanisms inthe detrusor directly. Noradrenaline (norepinephrine)is released in response to electrical stimulation ofdetrusor tissues in vitro, and the normal response ofdetrusor tissues to released noradrenaline is relaxation[Andersson, 1993].

III. PERIPHERAL NERVOUS CONTROL

II. CENTRAL NERVOUS CONTROL

Figure 1 : Components of the mic-turition reflex.

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Figure 2 : Activity in the micturitionreflex during storage. The pontinemicturition center is inhibited byimpulses from the prefrontal cortex,afferent impulses unable to initiatemicturition. Activities in the hypo-gastric and pudendal nerves keepthe bladder relaxed and the outflowregion contracted.

Figure 3 : Activity in the micturitionreflex during voluntary voiding. Theinhibitory impulses from theprefrontal cortex pontine micturitioncenter are removed and afferentimpulses are able to initiatemicturition. Activities in thehypogastric and pudendal nervesare inhibited, the outflow region isrelaxed, and the bladder iscontracted by the activity in thepelvic nerve.

Figure 4 : Detrusor overactivity.Despite the inhibitory impulses fromthe prefrontal to the cortex pontinemicturition center the enhanced (?)afferent impulses are able to initiatemicturition.

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The somatic innervation of the urethral rhabdosphincterand of some perineal muscles (for examplecompressor urethrae and urethrovaginal sphincter),is provided by the pudendal nerve. These fibersoriginate from sphincter motor neurons located in theventral horn of the sacral spinal cord (levels S2-S4)in a region called Onuf´s (Onufrowicz’s) nucleus).

Most of the sensory innervation of the bladder andurethra reaches the spinal cord via the pelvic nerveand dorsal root ganglia. In addition, some afferentstravel in the hypogastric nerve. The sensory nervesof the striated muscle in the rhabdosphincter travel inthe pudendal nerve to the sacral region of the spinalcord [Lincoln and Burnstock, 1993]. The most importantafferents for the micturition process are myelinated Aδ-fibres and unmyelinated C-fibres travelling in the pelvicnerve to the sacral spinal cord, conveying informationfrom receptors in the bladder wall to the spinal cord.The Aδ-fibres respond to passive distension and activecontraction, thus conveying information about bladderfilling [Janig and Morrison, 1986]. C-fibres have ahigh mechanical threshold and respond primarily tochemical irritation of the bladder mucosa [Habler etal., 1990] or cold [Fall et al., 1990]. Following chemicalirritation, the C-fibre afferents exhibit spontaneousfiring when the bladder is empty and increased firingduring bladder distension [Habler et al., 1990]. Thesefibres are normally inactive and are therefore termed”silent fibres”.

As pointed out previously, bladder control disorderscan be divided into two general categories: disordersof filling/storage and disorders of voiding [Wein, 2007].

Storage problems can occur as a result of weaknessor anatomical defects in the urethral outlet, causingstress urinary incontinence. Failure to store also occursif the bladder is overactive, as in the overactive bladder(OAB) syndrome. The prevalence varies with thecriteria used for diagnosis, but according to Irwin etal. (2006), using the ICS definition of 2002 [Abramset al., 2002], the overall prevalence of OAB, based oncomputer assisted telephone interviews (the EPICstudy) was 11.8%; rates were similar in men andwomen and increased with age [Irwin et al., 2006]. Asimilar study based on a cross Canada telephonesurvey found the prevalence of OAB to be 13 % in menand 14.7% in women [Herschorn et al., 2008]. OAB(symptomatic diagnosis) is often assumed to becaused by detrusor overactivity (DO; urodynamicdiagnosis), even if this does not always seem to bethe case [Hyman et al., 2001; Digesu et al., 2003;Hashim and Abrams, 2004; Aschkenazi et al., 2007].

DO/OAB can occur as a result of sensitization ofafferent nerve terminals in the bladder or outlet region,changes of the bladder smooth muscle secondary todenervation, or consequent upon damage to thecentral nervous system (CNS) inhibitory pathways(Figure 5), as can be seen in various neurologicaldisorders, such as multiple sclerosis, cerebrovasculardisease, Parkinson’s disease, brain tumors, and spinalcord injury [Ouslander, 2004]. Urinary retention andoverflow incontinence can be observed in patientswith urethral outlet obstruction (e.g. prostateenlargement), decreased detrusor contractility, orboth), neural injury, and/or diseases that damagenerves (e.g. diabetes mellitus), or in those who aretaking drugs that depress the neural control of thebladder or bladder smooth muscle directly [Wein,2007].

IV. PATHOGENESIS OF BLADDERCONTROL DISORDERS

Figure 5 : The diverse patho-physiology of detrusor overactivity.a) increased afferent activitygenerated within the detrusormuscle and/or the urothelium mayinitiate the micturition reflex. b) thecentral nervous system may beunable to control afferentinformation from the bladder. c)activation of the pontine micturitioncenter may occur more or lessindependent of afferent information.

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Normal bladder contraction in humans is mediatedmainly through stimulation of muscarinic receptors inthe detrusor muscle. Atropine resistance, i.e.contraction of isolated bladder muscle in response toelectrical nerve stimulation after pretreatment withatropine, has been demonstrated in most animalspecies, but seems to be of little importance in normalhuman bladder muscle [Andersson, 1993; Bayliss etal., 1999]. However, atropine-resistant (non-adrenergic,non-cholinergic: NANC) contractions have beenreported in normal human detrusor and may be causedmainly by adenosine triphosphate (ATP) [Andersson,1993; Bayliss et al., 1999, Andersson and Wein, 2004;Kennedy et al., 2007]. ATP acts on two families ofpurinergic receptors: an ion channel family (P2X) anda G-protein-coupled receptor family (P2Y). SevenP2X subtypes and eight P2Y subtypes have beenidentified. In several species (rabbit, cat, rat, andhuman), various studies suggested that multiplepurinergic excitatory receptors are present in thebladder [de Groat and Yoshimura, 2001]. Immuno-histochemical experiments with specific antibodiesfor different P2X receptors showed that P2X1 receptorsare the dominant subtype in membranes of rat detrusormuscle and vascular smooth muscle in the bladder.Excitatory receptors for ATP are present in para-sympathetic ganglia, afferent nerve terminals, andurothelial cells [de Groat and Yoshimura, 2001]. P2X3receptors, which have been identified in small-diameterafferent neurons in dorsal root ganglia, have alsobeen detected immunohistochemically in the wall ofthe bladder and ureter in a suburothelial plexus ofafferent nerves. In P2X3 knockout mice, afferentactivity induced by bladder distension was significantlyreduced [Cockayne et al., 2000; Ford et al., 2006;Ruggieri et al., 2006]. These data indicate thatpurinergic receptors are involved in mechanosensorysignaling in the nonprimate mammalian bladder.

A significant degree of atropine resistance may existin morphologically and/or functionally changedbladders, and has been reported to occur inhypertrophic bladders [Sjögren et al., 1982], interstitialcystitis [Palea et al., 1993], neurogenic bladders[Wammack et al., 1995], and in the aging bladder[Yoshida et al., 2001]. The importance of the NANCcomponent to detrusor contraction in vivo, normally,and in different micturition disorders, remains to beestablished.

The neurotransmitter ACh acts on two classes ofreceptors, the nicotinic and the muscarinic receptors.While the former play a role in the signal transductionbetween neurones or between neurones and skeletal

muscle (e.g. in the distal urethra), the signaltransduction between parasympathetic nerves andsmooth muscle of the detrusor involves muscarinicreceptors [Abrams and Andersson, 2007]. Importantly,the endogenous muscarinic receptor agonist ACh isnot necessarily derived only from parasympatheticnerves in the urinary bladder, but can also be formedand released non-neuronally by the urothelium[Bschleiper et al., 2007; Mansfield et al., 2005;Zarghooni et al., 2007]. Five subtypes of muscarinicreceptors have been cloned in humans and othermammalian species, which are designated M1-5[Caulfield and Birdsall 1998]. Based upon structuralcriteria and shared preferred signal transductionpathways, the subtypes can be grouped into M1, M3and M5 on the one hand and the subtypes M2 andM4 on the other. The former prototypically couple viapertussis toxin-insensitive Gq proteins to stimulationof a phospholipase C followed by elevation ofintracellular calcium and activation of a protein kinaseC, whereas the latter prototypically couple via pertussistoxin-sensitive Gi proteins to inhibition of adenylylcyclase and modulation of several ion channels[Caulfield and Birdsall 1998]. While sensitive moleculartechniques such as reverse transcriptase polymerasechain reaction can detect mRNA for all five subtypesin the mammalian bladder [Abrams et al., 2006: Hegde,2006], studies at the protein level, e.g. based uponradioligand binding, have typically detected only M2and M3 receptors, with the former dominatingquantitatively [Abrams et al., 2006: Hegde, 2006].Functional studies have implicated an involvementof M1 and M4 receptors (alongside with M2 receptors)in the prejunctional regulation of neurotransmitterrelease in the mammalian bladder, with M1 receptorsenhancing and M2 and M4 receptors inhibiting AChrelease [Braverman et al., 1998; D`Agostini et al.,1997]. However, most muscarinic receptors in theurinary bladder are located on smooth muscle andurothelial cells.

Apparently, most muscarinic receptors in the bladderare found on the smooth muscle cells of the detrusor.While the detrusor expresses far more M2 than M3receptors, it appears that detrusor contraction underphysiological conditions is largely if not exclusivelymediated by the M3 receptor [Hegde et al., 1997;Chess-Williams et al., 2001; Fetscher et al., 2002;Kories et al., 2003; Schneider et al., 2004a, b]. Studiesin knock-out mice confirm this conclusion [Matsui etal., 200; 2002; Stengel et al., 2002; Ehlert et al., 2007].Under physiological conditions M2 receptor-selectivestimulation causes little contraction [Schneider et al.,2005a], but rather appears to act mainly by inhibitingß-adrenoceptor-mediated detrusor relaxation [Hegdeet al., 1997; Ehlert et al., 2007; Matsui et al., 2003].It has been proposed that M2 receptors can alsodirectly elicit bladder contraction under pathologicalconditions [Braverman et al., 1998; 2002; 2003; 2006;Pontari et al., 2003] , but such observations have not

VI. MUSCARINIC RECEPTORS

V. BLADDER CONTRACTION

638

been confirmed by other investigators using distinctmethodological approaches [Schneider et al., 2005a;b].

Based upon the prototypical signalling pathway of M3receptors [Cauldfield and Birdsall, 1998] and thepresence of phospholipase C stimulation by muscarinicagonists in the bladder [Kories et al., 2003; Schneideret al., 2005a] it had originally been believed thatmuscarinic receptor-mediated contraction is largelymediated by an activation of phospholipase C[Ouslander, 2004]. While some earlier data hadsupported this concept, it now appears clear that, atleast in rat, mice and humans, muscarinic receptor-mediated bladder contraction occurs largelyindependent of phospholipase C [Schneider et al.,2004; Wegener et al., 2004; Frazier et al., 2007].Rather, alternative signalling pathways such asopening of L-type calcium channels and activation ofa rho-kinase (Figure 6) appear to contribute tomuscarinic receptor-mediated bladder contraction ina major way [Frazier et al., 2008].

More recently, muscarinic receptors have also beenidentified in the urothelium [Chess-Williams, 2002;Kumar et al., 2005]. Similarly to the findings in bladdersmooth muscle, the muscarinic receptors in theurothelium mainly belong to the M2 and M3 subtype,with the former dominating quantitatively [Mansfieldet al., 2005; Bschleiper et al., 2007]. At present thefunctional role of muscarinic receptors in the urotheliumhas largely been studied indirectly, i.e. by investigatingthe effects of urothelium removal or of administrationof pharmacological inhibitors. These data indicatethat muscarinic stimulation of the urothelium causesrelease of an as yet unidentified factor which inhibitsdetrusor contraction [Hawthorn et al., 2000; Wuest

et al., 2005; Sadananda et al., 2008]. Some dataindicate that muscarinic receptors in the urotheliummay partly act by releasing nitric oxide (NO)[Andersson et al., 2008a]. Thus, it appears thatmuscarinic receptors in the urothelium also contributeto the regulation of overall bladder function but theirspecific roles in health and disease have not been fullyestablished [Andersson et al., 2008b].

Based upon the involvement of muscarinic receptorsin physiological voiding contractions of the bladder,numerous studies have explored whether anoveractivity of the muscarinic system may play acausative role in bladder dysfunction. This couldinvolve, e.g., an enhanced expression of suchreceptors and/or an increased functional respon-siveness. In vitro, an increased sensitivity to muscarinicreceptor stimulation was found in both idiopathic andneurogenic overactive human detrusors (Stevens etal. 2006). However, according to Michel andBarendrecht [2008] the overall balance of availablestudies suggests that the muscarinic receptor systemis not hyperactive under conditions of DO and, ifanything, can be even hypoactive [Michel andBarendrecht, 2008]. This does not exclude acontribution to DO of ACh and muscarinic receptorstimulation during bladder filling (see below). It appearsthat the contribution of muscarinic mechanisms to theoverall regulation of bladder contractility decreases infavour of non-cholinergic mechanisms underpathological conditions [Yoshida et al., 2001; 2008;Rapp et al 2005]. These observations may help toexplain the moderate efficacy of muscarinic receptorantagonists relative to placebo in controlled clinicalstudies [Herbison et al., 2003; Chapple et al., 2005;2008; Novara et al., 2008; Shamliyan et al., 2008].

Figure 6 : Muscarinic M3receptor-mediated detrusoractivation. Calcium influxand activation of the Rho-kinase system are the mainpathways mediating activa-tion of the contractilesystem.

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It has been estimated that more than 50 million peoplein the developed world are affected by urinaryincontinence, and an abundance of drugs has beenused for treatment (Table 2). As underlined by severalother subcommittees, drugs may be efficacious insome patients, but they do have side effects, andfrequently are not continued indefinitely. Hence itwould be worth considering them as an adjunct toconservative therapy.

Mechanism of action. Antimuscarinics block, moreor less selectively, muscarinic receptors [Abrams andAndersson, 2007]. The common view is that inOAB/DO, the drugs act by blocking the muscarinicreceptors on the detrusor muscle, which are stimulatedby ACh, released from activated cholinergic(parasympathetic) nerves. Thereby, they decreasethe ability of the bladder to contract. However,antimuscarinic drugs act mainly during the storagephase, decreasing urgency and increasing bladdercapacity, and during this phase, there is normally noparasympathetic input to the lower urinary tract[Andersson, 2004]. Furthermore, antimuscarinics areusually competitive antagonists. This implies thatwhen there is a massive release of ACh, as duringmicturition, the effects of the drugs should bedecreased, otherwise the reduced ability of thedetrusor to contract would eventually lead to urinaryretention. Undeniably, high doses of antimuscarinics

can produce urinary retention in humans, but in thedose range used for beneficial effects in OAB/DO,there is little evidence for a significant reduction of thevoiding contraction [Finney et al., 2006; Figure 7].However, there is good experimental evidence that thedrugs act during the storage phase by decreasingthe activity in afferent nerves (both C- and Aδ -fibres)from the bladder [De Laet et al., 2006; Ijima et al.,2007].

As mentioned previously, muscarinic receptors arefound on bladder urothelial cells where their densitycan be even higher than in detrusor muscle. The roleof the urothelium in bladder activation has attractedmuch interest [Andersson, 2002; Birder and de Groat,2007], but whether the muscarinic receptors onurothelial cells can influence micturition has not yetbeen established. Yoshida and colleagues [2004;2006; 2008] found that there is basal ACh release inhuman bladder. This release was resistant totetrodotoxin and much diminished when the urotheliumwas removed; thus, the released ACh was probablyof non-neuronal origin and, at least partly, generatedby the urothelium. There is also indirect clinicalevidence for release of ACh during bladder filling.Smith and co-workers [1974] found that in patients withrecent spinal-cord injury, inhibition of ACh breakdownby use of cholinesterase inhibitors could increaseresting tone and induce rhythmic contractions in thebladder. Yossepowitch and colleagues [2001] inhibitedACh breakdown with edrophonium in a series ofpatients with disturbed voiding or urinary incontinence.They found a significant change in sensation anddecreased bladder capacity, induction or amplificationof involuntary detrusor contractions, or significantlydecreased detrusor compliance in 78% of the patientswith the symptom pattern of overactive bladder, butin no patients without specific complaints suggestingDO. Thus, during the storage phase, ACh and ATP maybe released from both neuronal and non-neuronalsources (eg, the urothelium) and directly or indirectly

I. ANTIMUSCARINIC(ANTICHOLINERGIC) DRUGS

B. DRUGS USED FORTREATMENT OF OVERACTIVE

BLADDER SYMPTOMS/DETRUSOR OVERACTIVITY

Figure 7 : Rationale for use ofantimuscarinics for treatment ofOAB/DO. Blockade of muscarinicreceptors at both detrusor and non-detrusor sites may prevent OABsymptoms and DO without depres-sing the contraction during voiding

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Table 2. Drugs used in the treatment of OAB/ DO. Assessments according to the Oxford system (modified)

Level of evidence Grade of recommendation

Antimuscarinic drugs Tolterodine 1 ATrospium 1 ASolifenacin 1 ADarifenacin 1 AFesoterodine 1 APropantheline 2 BAtropine, hyoscyamine 3 C

Drugs acting on membrane channelsCalcium antagonists 2 DK-Channel openers 2 D

Drugs with mixed actionsOxybutynin 1 APropiverine 1 AFlavoxate 2 D

AntidepressantsImipramine 3 CDuloxetine 2 C

Alpha-AR antagonistsAlfuzosin 3 CDoxazosin 3 CPrazosin 3 CTerazosin 3 CTamsulosin 3 C

Beta-AR antagonistsTerbutaline (beta 2) 3 CSalbutamol (beta 2) 3 CYM-178 (beta 3) 2 B

PDE-5 Inhibitors+(Sildenafil, Taladafil, Vardenafil) 2 B

COX-inhibitorsIndomethacin 2 CFlurbiprofen 2 C

ToxinsBotulinum toxin (neurogenic)*** 2 ABotulinum toxin (idiopathic)*** 3 BCapsaicin (neurogenic)** 2 CResiniferatoxin (neurogenic)** 2 C

Other drugsBaclofen* 3 C

Hormones Estrogen 2 CDesmopressin# 1 A

+(male LUTS/OAB); * intrathecal; ** intravesical; *** bladder wall; #nocturia (nocturnal polyuria), caution hypona-tremia, especially in the elderly!

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(by increasing detrusor smooth muscle tone, Figures8, 9 and 10) excite afferent nerves in the suburotheliumand within the detrusor. These mechanisms may beimportant in the pathophysiology of OAB/DO andrepresent possible targets for antimuscarinic drugs.

Pharmacologic properties. Generally, antimus-carinics can be divided into tertiary and quaternaryamines [Guay, 2003, Abrams and Andersson, 2007].They differ with regards to lipophilicity, molecularcharge, and even molecular size, tertiary compoundsgenerally having higher lipophilicity and molecularcharge than quaternary agents. Atropine, darifenacin,fesoterodine (and its active metabolite 5-hydroxymethyl-tolterodine), oxybutynin, propiverine,solifenacin, and tolterodine, are tertiary amines. Theyare generally well absorbed from the gastrointestinaltract and should theoretically be able to pass into theCNS, dependent on their individual physicochemicalproperties. High lipophilicity, small molecular size,and less charge will increase the possibilities to passthe blood brain barrier, but in some cases, such astrospium, darifenacin, and fesoterodine, that iscompensated by active transport out of the CNS bythe product of the MDR1 gene (P-glykoprotein, seeTable 3). Quaternary ammonium compounds, likepropantheline and trospium, are not well absorbed,pass into the CNS to a limited extent, and have a lowincidence of CNS side effects [Guay 2003]. They stillproduce well-known peripheral antimuscarinic sideeffects, such as accommodation paralysis,constipation, tachycardia, and dryness of mouth.

Many antimuscarinics are metabolized by the P450enzyme system to active and/or inactive metabolites[Guay 2003]. The most commonly involved P450enzymes are CYP2D6, and CYP3A4. The metabolicconversion creates a risk for drug-drug interactions,resulting in either reduced (enzyme induction) or

increased (enzyme inhibition, substrate competition)plasma concentration/effect of the antimuscarinic and/or interacting drug. Antimuscarinics secreted by therenal tubules (eg trospium) may theoretically be ableto interfere with the elimination of other drugs usingthis mechanism.

Antimuscarinics are still the most widely used treatmentfor urgency and urgency incontinence [Andersson,2004]. However, currently used drugs lack selectivityfor the bladder, and effects on other organ systems(Figure 11) may result in side effects, which limit theirusefulness. For example, all antimuscarinic drugs arecontraindicated in untreated narrow angle glaucoma.

Theoretically, drugs with selectivity for the bladdercould be obtained if the subtype(s) mediating bladdercontraction and those producing the main side effectsof antimuscarinic drugs were different. Unfortunately,this does not seem to be the case. One way of avoidingmany of the antimuscarinic side effects is to administerthe drugs intravesically. However, this is practical onlyin a limited number of patients.

Several antimuscarinic drugs are and have been usedfor treatment of OAB/DO. For some of them,documentation of effects is not based on randomizedcontrolled trials (RCTs) satisfying currently requiredcriteria, and some drugs can be considered as obsolete(e.g., emepronium). Information on these drugs hasnot been included, but can be found elsewhere[Andersson, 1988; Andersson et al., 1999].

The clinical relevance of efficacy of antimuscarinicdrugs relative to placebo has been questioned.Herbison et al. [2003] stated in a widely discussedarticle: “Anticholinergics produce significantimprovements in overactive bladder symptomscompared with placebo.

Figure 8 : The hypothetical role ofacetylcholine (ACh) in the generationof DO) and OAB. During bladder filling,there is no activity in the para-sympathetic outflow from the bladder.However, the myocytes have a spon-taneous (myogenic) contractile activitythat generates afferent nerve activity(C-fibres and Ad-fibres). In DObladders, there are areas of “patchydenervation” and ACh in low concen-trations is “leaking” from the nerves.This enhances the sponta-neousactivity and the basal afferent nerveactivity (“afferent noise”). This meansthat the Ad-fibre activity, generatedby bladder distension, can initiate themicturition reflex at low degrees of

bladder filling. Antimuscarinics in therapeutically recommended doses can inhibit the effects of these lowconcentrations of acetylcholine, but not of the high concentrations necessary for the generating the voidingcontraction (requiring efferent nerve activity). Structural changes in the bladder (e.g., secondary to outflowobstruction) can generate local factors, such as prostaglandins and endothelins, which also can contributeto enhancement of the spontaneous activity.

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Figure 9 : The hypothetical role ofacetylcholine (ACh) in the generationof DO) and OAB. During bladder filling,there is no activity in theparasympathetic outflow from thebladder. However, the myocytes havea spontaneous (myogenic) contractileactivity that generates afferent nerveactivity (C-fibres and Ad-fibres). In DObladders, there are areas of “patchydenervation” and ACh in lowconcentrations is “leaking” from thenerves. This enhances thespontaneous activity and the basalafferent nerve activity (“afferentnoise”). This means that the Ad-fibreactivity, generated by bladderdistension, can initiate the micturitionreflex at low degrees of bladder filling.Antimuscarinics in therapeutically

recommended doses can inhibit the effects of these low concentrations of acetylcholine, but not of the highconcentrations necessary for the generating the voiding contraction (requiring efferent nerve activity).Structural changes in the bladder (e.g., secondary to outflow obstruction) can generate local factors, suchas prostaglandins and endothelins, which also can contribute to enhancement of the spontaneous activity.

Figure 10 : Distension of the bladderand shape-change of the urothelium(U) will generate and release differentsignaling molecules, including ATPand acetylcholine (ACh), whicheither directly or by action via theinterstitial cells (IC) will initiateactivity in the suburothelial afferentnerves. Antimuscarinics may inhibitthis ACh-induced activation. GC =glycocalix layer; DRG = dorsal rootganglion.

Figure 11 : Important sites of actionof antimuscarinics.

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The benefits are, however, of limited clinicalsignificance” Large meta-analyses of studiesperformed with the currently most widely used drugs[Chapple et al., 2005; 2008; Novara et al., 2008],clearly show that antimuscarinics are of significantclinical benefit. Novara et al. [2008] reviewed 50 RCTsand 3 pooled analyses, which they considered ofgood methodological quality. They concluded that stillmore clinical studies are needed to decide which ofthe drugs should be used as first-, second-, or third-line treatment. Reviewing information from more than12,000 references (Figure 12), Chapple et al. [2008],based their conclusions (“antimuscarinics areefficacious, safe, and well tolerated treatments”) on73 RCTs selected for their meta-analysis. It wasrecommended that since the profiles of each drug(see below) and dosage differ, these factors shouldbe considered in making treatment choices.

The consequence of this is that none of theantimuscarinic drugs in common clinical use(darifenacin, fesoterodine, oxybutynin, propiverine,solifenacin, tolterodine or trospium) is ideal as a first-line treatment for all OAB/DO patients. Optimaltreatment should be individualized, implying that thepatient´s co-morbidities and concomitant medications,and the pharmacological profiles of the different drugs,should be taken into consideration [Chapple et al.,2008].

Below data on the different antimuscarinics arepresented. The amount of information for the individualdrugs varies, and so does the degree of details fromthe different studies presented. However, theinformation has been chosen to give a reasonableefficacy and adverse effect profile of each individualdrug.

1. ATROPINE SULFATE

Atropine (dl-hyoscyamine) is rarely used for treatmentof OAB/DO because of its systemic side effects, whichpreclude its use as an oral tratment. However, inpatients with neurogenic DO, intravesical atropinemay be effective for increasing bladder capacity withoutcausing any systemic adverse effects, as shown inopen pilot trials [Ekström et al., 1992; Glickman etal., 1995; Deaney et al., 1998; Enskat et al., 2001;Fader et al 2007]. It appears that intravesical atropinemay be as effective as intravesical oxybutynin inpatients with neurogenic DO [Fader et al., 2007].

The pharmacologically active antimuscariniccomponent of atropine is l-hyoscyamine. Althoughstill used, few clinical studies are available to evaluatethe antimuscarinic activity of l-hyoscyamine sulfate[Muskat et al., 1996]. For assessment, see Table 2.

2. PROPANTHELINE BROMIDE

Propantheline is a quaternary ammonium compound,non-selective for muscarinic receptor subtypes, which

has a low (5 to 10%) and individually varying biologicalavailability. It is metabolized (metabolites inactive)and has a short halflife (less than 2 h) [Beermann etal., 1972]. It is usually given in a dose of 15 to 30 mg4 times daily, but to obtain an optimal effect, individualtitration of the dose is necessary, and often higherdosages are required. Using this approach in 26patients with detrusor overactivity contractions [Blaivaset al., 1980] in an open study obtained a completeclinical response in all patients but one, who did nottolerate more than propantheline 15 mg four timesdaily. The range of dosages varied from 7.5 to 60 mgfour times daily. In contrast, Thüroff et al. [1991]comparing the effects of oxybutynin 5 mg three timesdaily, propantheline 15 mg three times daily, andplacebo, in a randomized, double-blind, multicentertrial on the treatment of frequency, urgency andincontinence related to DO (154 patients), found nodifferences between the placebo and propanthelinegroups. In another randomized comparative trial withcrossover design (23 women with idiopathic DO), andwith dose titration, Holmes et al. [1991] found nodifferences in efficacy between oxybutynin andpropantheline. Controlled randomized trials (n=6)reviewed by Thüroff et al [1998], confirmed a positive,but varying, response to the drug.

Although the effect of propantheline on OAB/DO hasnot been well documented in controlled trials satisfyingstandards of today, it can be considered effective,and may, in individually titrated doses, be clinicallyuseful (Table 2). No new studies on the use of this drugfor treatment of OAB/DO seem to have beenperformed during the last decade.

3. TROSPIUM CHLORIDE

Trospium is a quaternary ammonium compound witha biological availability less than 10% [Fusgen andHauri, 2000; Doroshyenko et al., 2005]. The drug hasa plasma half-life of approximately 20 h, and is mainly(60% of the dose absorbed) eliminated unchanged inthe urine. The concentration obtained in urine seemsto be enough to affect the mucosal signaling systemin a rat model [Kim et al., 2006]. Whether or not itcontributes to the clinical efficacy of the drug remainsto be established.

Trospium is not metabolized by the cytochrome P450enzyme system [Beckmann-Knopp et al., 1999;Doroshyenko et al., 2005]. It is expected to cross theblood-brain to a limited extent and seems to have nonegative cognitive effects [Fusgen and Hauri, 2000;Todorova et al., 2001; Widemann et al., 2002].

Trospium has no selectivity for muscarinic receptorsubtypes. In isolated detrusor muscle, it was morepotent than oxybutynin and tolterodine to antagonizecarbachol-induced contractions [Uckert et al., 2000].

Several RCTs have documented positive effects oftrospium both in neurogenic [Stöhrer, et al., 1991;

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Figure 12 : Trials included in metanalysis. From Chapple et al. , Eur Urol 2005; 48: 5-26 and Chapple et al.,Eur Urol. 2008 Sep;54(3):543-62.

Table 3. Some physico-chemical properties of antimuscarinics (Kay et al., AUA presentation, 2009)

5-HMT Fesoterodine1 Tolterodine Trospium2 Solifenacin2 Darifenacin2 Oxybutynin2

logD, Octanol-Water Ratio 0.74 1.42 1.83 -1.22 1.69 2.7 > 3.3

Permeability x106 (cm/s) 6.49 35.5 23.4 0.57 31.5 28.5 30.3

Brain-Blood Ratio3 0.04-0.07 0.1-0.32 NA NA NA NA

PgP Substrate Yes Yes NA Yes No Yes NA

1 Fesoterodine is not detectable in blood after oral administration in humans due to rapid and extensive hydrolysis to 5-HMT by non-specific esterases.

2 Literature data, except PBEC permeability3 Drug-related radioactivityNA : Not Available

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Madersbacher et al., 1995; Menarini et al., 2006] andnon-neurogenic DO [Allousi et al., 1998; Cardozo etal., 2000; Junemann et al., 2000; Halaska et al., 2003;Zinner et al., 2004a; Rudy et al., 2006; Staskin et al.,2007; Dmochowski et al., 2008]. In a placebo-controlled, double blind study on patients withneurogenic DO [Stöhrer et al, 1991], the drug wasgiven twice daily in a dose of 20 mg over a 3-weekperiod. It increased maximum cystometric capacity,decreased maximal detrusor pressure and increasedcompliance in the treatment group, whereas no effectswere noted in the placebo group. Side effects werefew and comparable in both groups. In another RCTincluding patients with spinal cord injuries andneurogenic DO, trospium and oxybutynin wereequieffective; however, trospium seemed to havefewer side effects [Madersbacher et al., 1995].

The effect of trospium in urgency incontinence hasbeen documented in several RCTs. Allousi et al. [1998]compared the effects of the drug with those of placeboin 309 patients in a urodynamic study of 3 weeksduration. Trospium 20 mg was given twice daily.Significant increases were noted in volume at firstinvoluntary contraction and in maximum bladdercapacity. Cardozo et al. [2000] investigated 208patients with DO, who were treated with trospium 20mg twice daily for two weeks. Also in this study,significant increases were found in mean volume atfirst unstable contraction (from 233 to 299 ml; placebo254 to 255 ml) and in maximum bladder capacity(from 329 to 356 ml; placebo 345 to 335 ml) in thetrospium treated group. Trospium was well toleratedwith similar frequency of adverse effects as in theplacebo group. Jünemann et al. [2000] comparedtrospium 20 mg twice daily with tolterodine 2 mg twicedaily in a placebo-controlled double-blind study on232 patients with urodynamically proven DO, urgencyincontinence without demonstrable DO, or mixedincontinence. Trospium reduced the frequency ofmicturition, which was the primary endpoint, morethan tolterodine and placebo, and also reduced thenumber of incontinence episodes more than thecomparators. Dry mouth was comparable in thetrospium and tolterodine groups (7 and 9%,respectively).

Halaska et al. [2003] studied the tolerability and efficacyof trospium chloride in doses of 20 mg twice daily forlong-term therapy in patients with urgency syndrome.The trial comprised a total of 358 patients with urgencysyndrome or urgency incontinence. After randomisationin the ratio of 3:1, participants were treatedcontinuously for 52 weeks with either trospium chloride(20 mg twice daily) or oxybutynin (5 mg twice daily).Urodynamic measurements were performed at thebeginning, and at 26 and 52 weeks to determine themaximal cystometric bladder capacity. Analysis of themicturition diary clearly indicated a reduction of themicturition frequency, incontinence frequency, and a

reduction of the number of urgency episodes in bothtreatment groups. Mean maximum cystometric bladdercapacity increased during treatment with trospiumchloride by 92 ml after 26 weeks and 115 ml after 52weeks (P=0.001). Further comparison with oxybutynindid not reveal any statistically significant differencesin urodynamic variables between the drugs. Adverseevents occurred in 65% of the patients treated withtrospium and 77% of those treated with oxybutynin.The main symptom encountered in both treatmentgroups was dryness of the mouth. An overallassessment for each of the drugs revealed acomparable efficacy level and a better benefit-riskratio for trospium than for oxybutynin due to bettertolerability.

Zinner et al. [2004] treated 523 patients with symptomsassociated with OAB and urgency incontinence with20 mg trospium twice daily or placebo in a 12-week,multicenter, parallel, double-blind, placebo controlledtrial. Dual primary end points were change in averagenumber of toilet voids and change in urgencyincontinent episodes per 24 hours. Secondary efficacyvariables were change in average of volume per void,voiding urgency severity, urinations during day andnight, time to onset of action and change inIncontinence Impact Questionnaire. By week 12,trospium significantly decreased average frequencyof toilet voids per 24 hours (-2.37;placebo -1,29) andurgency incontinent episodes (-59%;placebo -44%).It significantly increased average volume per void (32ml; placebo: 7.7) ml, and decreased average urgencyseverity and daytime frequency. All effects occurredby week 1 and all were sustained throughout thestudy. Nocturnal frequency decreased significantlyby week 4 (-0.43; placebo: 0.17) - and IncontinenceImpact Questionnaire scores improved at week 12.Trospium was well tolerated. The most common sideeffects were dry mouth (21.8%; placebo 6.5%),constipation (9.5%; placebo 3.8%) and headache(6.5%; placebo 4.6%).

In a large US multicenter trial with the same design,and including 658 patients with OAB, Rudy et al.[2006] confirmed the data by Zinner et al [2004], bothwith respect to efficacy and adverse effects.

An extended release formulation of trospium allowingonce daily dosing, has been introduced and and itseffects tested in controlled trials [Staskin et al., 2008;Dmochowski et al., 2008]. These RCTs demonstratedsimilar efficacy as found with previous formulations.The most frequent side effects were dry mouth (12.9%;placebo 4.6) and constipation (7.5%; placebo 1.8)[Dmochowski et al., 2008].

Intravesical application of trospium may be aninteresting alternative. Frölich et al. [1998] performeda randomised, single-blind, placebo-controlled, mono-centre clinical trial in 84 patients with urgency orurgency incontinence. Compared to placebo, intra-

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vesical trospium produced a significant increase inmaximum bladder capacity and a decrease of detrusorpressure accompanied by an increase of residualurine. There was an improvement in uninhibitedbladder contractions. No adverse events werereported. Interestingly, intravesical trospium does notseem to be absorbed [Walter et al., 1999], thus offeringan opportunity for treatment with minimal systemicantimuscuscarinic effects.

Trospium has a well-documented effect in OAB/DO,and tolerability and safety seems acceptable (Table 2).

4. TOLTERODINE TARTRATE

Tolterodine is a tertiary amine, rapidly absorbed andextensive metabolized by the cytochrome P450 system(CYP 2D6). The major active 5-hydroxymethylmetabolite (5-HMT) has a similar pharmacologicalprofile as the mother compound [Nilvebrant et al.,1997], and significantly contributes to the therapeuticeffect of tolterodine [Brynne et al., 1997; Brynne et al.,1998]. Both tolterodine and 5-HMT have plasma half-lifes of 2-3 h, but the effects on the bladder seem tobe more long-lasting than could be expected fromthe pharmacokinetic data. Urinary excretion oftolterodine accounted for <1-2.4 % of the dose; 5 –14% of 5-HMT is eliminated in the urine [Brynne et al.,1997]. Whether or not the total antimuscarinic activityof unchanged tolterodine and 5-HMT excreted in urineis sufficient to exert any effect on the mucosal signalingmechanisms has not been established. However, thepreliminary studies by Kim et al. [2005] and Chuanget al., [2008], do not support such an effect.

The relatively low lipophilicity of tolterodine and evenlesser one of 5-HMT, implies limited propensity topenetrate into the CNS, which may explain a lowincidence of cognitive side effects [Hills et al., 1998,Clemett et al., 2001; Salvatore et al., 2008]. However,tolterodine may disturb sleep in subjects unable toform the even less lipophilic 5-HMT due to a lowactivity of CYP 2D6 [Diefenbach et al., 2008].

Tolterodine has no selectivity for muscarinic receptorsubtypes, but is claimed to have functional selectivityfor the bladder over the salivary glands [Stahl et al.,1995; Nilvebrant et al. 1997b]. In healthy volunteers,orally given tolterodine in a high dose (6.4 mg) had apowerful inhibitory effect on micturition and alsoreduced stimulated salivation 1 hour afteradministration of the drug [Stahl et al., 1995]. However,5 hours after administration, the effects on the urinarybladder were maintained, whereas no significanteffects on salivation could be demonstrated.

Tolterodine is available as immediate-release (TOLT-IR; 1 or 2 mg; twice daily dosing) and extended-release (TOLT-ER) forms (2 or 4 mg; once dailydosing). The ER form seems to have advantagesover the IR form in terms of both efficacy and tolerability[Van Kerrebroeck et al. 2001].

Several randomised, double blind, placebo-controlledstudies on patients with OAB/DO (both idiopathic andneurogenic DO), have documented a significantreduction in micturition frequency and number ofincontinence episodes [Hills et al., 1998; Clemett etal., 2001; Salvatore et al., 2008]. Comparative RCTssuch as the OBJECT (Overactive Bladder: JudgingEffective Control and Treatment), and the OPERA(Overactive Bladder; Performance of ExtendedRelease Agents) studies have further supported itseffectiveness.

The OBJECT trial compared oxybutynin ER (OXY-ER) 10 mg once daily with TOLT-IR 2 mg twice daily[Appell et al., 2001] in a 12-week randomized, doubleblind, parallel-group study including 378 patients withOAB. Participants had between 7 and 50 episodes ofurgency incontinence per week and 10 or more voidsin 24 hours. The outcome measures were the numberof episodes of urgency incontinence, total incontinence,and micturition frequency at 12 weeks adjusted forbaseline. At the end of the study, OXY-ER was foundto be significantly more effective than TOLT-IR in eachof the main outcome measures adjusted for baseline(see also below: oxybutynin chloride). Dry mouth, themost common adverse event, was reported by 28%and 33% of participants taking OXY-ER and TOLT-IR,respectively. Rates of central nervous system andother adverse events were low and similar in bothgroups. The authors concluded that OXY-ER wasmore effective than TOLT-IR and that the rates of drymouth and other adverse events were similar in both

treatment groups.

In the OPERA study [Diokno et al., 2003], OXY-ER at10 mg/d or TOLT-ER at 4 mg/d were given for 12weeks to women with 21 to 60 urgency incontinenceepisodes per week and an average of 10 or morevoids per 24 hours. Episodes of incontinence episodes(primary end point), total (urgency and non urgency)incontinence, and micturition were recorded in seven24-hour urinary diaries at baseline and at weeks 2, 4,8 and 12 and compared. Adverse events were alsoevaluated. Improvements in weekly urgencyincontinence episodes were similar for the 790 womenwho received OXY-ER (n=391) or TOLT-ER (n=399).OXY-ER was significantly more effective than TOLT-ER in reducing micturition frequency, and 23.0% ofwomen taking OXY-ER reported no episodes of urinaryincontinence compared with 16.8% of women takingTOLT-ER. Dry mouth, usually mild, was more commonwith OXY-ER. Adverse events were generally mildand occurred at low rates, with both groups havingsimilar discontinuation of treatment due to adverseevents. The conclusions were that reductions in weeklyurgency incontinence and total incontinence episodeswere similar with the two drugs. Dry mouth was morecommon with OXY-ER, but tolerability was otherwisecomparable; including adverse events involving thecentral nervous system.

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In the ACET (Antimuscarinic Clinical EffectivenessTrial) [Sussman and Garely, 2002] study, whichconsisted of two trials, patients with OAB wererandomized to 8 weeks of open-label treatment witheither 2 mg or 4 mg of once-daily TOLT-ER (studyone) and to 5 mg or 10 mg of OXY-ER (study two). Atotal of 1289 patients were included. Fewer patientsprematurely withdrew from the trial in the TOLT-ER 4mg group (12%) than either the OXY-ER 5 mg (19%)or OXY-ER 10 mg groups (21%). More patients in theOXY-ER 10 mg group than the TOLT-ER 4 mg groupwithdrew because of poor tolerability (13% vs. 6%).After 8 weeks, 70% of patients in the TOLT-ER 4 mggroup perceived an improved bladder condition,compared with 60% in the TOLT-ER 2 mg group, 59%in the OXY-ER 5 mg group and 60% in the OXY-ER10 mg group. Dry mouth was dose-dependent withboth agents, although differences between dosesreached statistical significance only in the oxybutynintrial (OXY-ER 5 mg vs. OXY-ER 10 mg; p=0.05).Patients treated with TOLT-ER 4 mg reported asignificantly lower severity of dry mouth comparedwith OXY-ER 10 mg. The conclusion that the findingssuggest improved clinical efficacy of TOLT-ER (4 mg)than of OXY-ER (10 mg) is weakened by the the openlabel design of the study.

Zinner et al. [2002] evaluated the efficacy, safety, andtolerability of TOLT-ER in older (> or =65) and younger(<65) OAB patients, in a 12-week RCT including 1015patients with urgency incontinence and urinaryfrequency. Patients were randomized to treatmentwith TOLT-ER 4 mg once daily (n = 507) or placebo(n = 508) for 12 weeks. Efficacy, measured withmicturition charts (incontinence episodes, micturitions,volume voided per micturition) and subjective patientassessments, safety, and tolerability endpoints wereevaluated, relative to placebo. Compared with placebo,significant improvements in micturition chart variableswith TOLT-ER showed no age-related differences.Dry mouth (of any severity) was the most commonadverse event in both the TOLT-ER and placebotreatment arms, irrespective of age (<65: ER 22.7%,placebo 8.1%; > or =65: ER 24.3%, placebo 7.2%).A few patients (< 2%) experienced severe dry mouth.No central nervous system (cognitive functions werenot specifically studied), visual, cardiac (perelectrocardiogram), or laboratory safety concernswere noted in this study. Withdrawal rates due toadverse events on TOLT-ER 4 mg once daily werecomparable in the two age cohorts (<65: 5.5%; > or=65: 5.1%).

The central symptom in the OAB syndrome is urgency.Freeman et al. [2003] presented a secondary analysisof a double-blind, placebo-controlled study evaluatingthe effect of once-daily TOLT-ER on urinary urgencyin patients with OAB. Patients with urinary frequency(eight or more micturitions per 24 hours) and urgencyincontinence (five or more episodes per week) were

randomized to oral treatment with TOLT-ER 4 mgonce daily (n=398) or placebo (n=374) for 12 weeks.Efficacy was assessed by use of patient perceptionevaluations. Of patients treated with TOLT-ER, 44%reported improved urgency symptoms (compared with32% for placebo), and 62% reported improved bladdersymptoms (placebo, 48%). The proportion of patientsunable to hold urine upon experiencing urgency wasdecreased by 58% with TOLT-ER, compared with32% with placebo (P<.001).

In the IMprovement in Patients: Assessingsymptomatic Control with Tolterodine ER (IMPACT)study [Elinoff et al., 2005], the efficacy of TOLT-ER forpatients’ most bothersome OAB symptom wasinvestigated in an open label, primary care setting.Patients with OAB symptoms for >3 months receivedTOLT-ER (4 mg once daily) for 12 weeks. By week 12,there were significant reductions in patients’ mostbothersome symptom: incontinence, urgencyepisodes, nocturnal and daytime frequency. The mostcommon adverse events were dry mouth (10%) andconstipation (4%), and it was concluded that in primarycare practice, bothersome OAB symptoms can beeffectively and safely treated with TOLT-ER, even inpatients with comorbid conditions.

Various aspects of the efficacy and tolerability oftolterodine have been further documented in a numberof RCTs [Dmochowski et al., 2007a; 2007; Baruchaet al., 2008; Choo et al., 2008; Coyne et al., 2008;Rogers et al., 2008; Rovner et al., 2008a; see further:Novara et al, 2008, Chapple et al., 2008]. Importantly,the QTc effects of tolterodine were determined in acrossover-designed QT study of recommended (2 mgtwice daily) and supratherapeutic (4 mg twice daily)doses of tolterodine, moxifloxacin (400 mg once daily),and placebo was performed. No subject receivingtolterodine exceeded the clinically relevant thresholdsof 500 ms absolute QTc or 60ms change from baseline,and it was concluded that tolterodine does not havea clinically significant effect on QT interval [Malhotraet al., 2007].

Olshansky et al. [2008] compared in a randomized,placebo-controled, double blind, crossover study, theeffects on heart rate of TOLT-ER 4mg/day with thoseof darifenacin 15 mg/day and placebo in 162 healthyvolunteers. They found that tolterodine, but notdarifenacin and placebo, significantly increased meanheart rate per 24 hours. The proportion of subjects withan increase > 5 beats/min was significantly greater inthose receiving TOLT-ER (1 out of 4) than withdarifenacin (1 out of 10).

In a prospective, open study, Song et al. [2006]compared the effects of bladder training and/ortolterodine as first line treatment in female patients withOAB. One hundred and thirty-nine female patientswith OAB were randomized to treatment with bladdertraining (BT), tolterodine (2 mg twice daily) or both for12 weeks. All treatments were efficacious, however,

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combination therapy was the most effective.Mattiasson et al. [2003] compared the efficacy oftolterodine 2 mg twice daily plus simplified bladdertraining (BT) with tolterodine alone in patients withOAB in a multicenter single blind study. At the end ofthe study the median percentage reduction in voidingfrequency was greater with tolterodine + BT than withtolterodine alone (33% vs. 25%; p<0.001), while themedian percentage increase in volume voided pervoid was 31% with tolterodine + BT and 20% withtolterodine alone (p<0.001). There was a median of81% fewer incontinence episodes than at baselinewith tolterodine alone, which was not significantlydifferent from that with tolterodine + BT (-87%). It wasconcluded that the effectiveness of tolterodine 2mgtwice daily can be augmented by a simplified BTregimen. However, Millard et al. [2004] investigatedwhether the combination of tolterodine plus a simplepelvic floor muscle exercise program would provideimproved treatment benefits compared with tolterodinealone in 480 patients with OAB. Tolterodine therapyfor 24 weeks resulted in significant improvement inurgency, frequency, and incontinence, however, noadditional benefit was demonstrated for a simplepelvic floor muscle exercise program.

The beneficial effect of TOLT-ER in men with benignprostatic enlargement (BPE) and LUTS, includingOAB, has been well documented. Both asmonotherapy, but in particularly in combination withα-adenoceptor (AR) antagonist, TOLT-ER was foundeffective [Kaplan et al., 2006; Höfner et al., 2007;Kaplan et al., 2008a; 2008b; Rovner et al., 2008;Roehrborn et al., 2008]. This effect was obtainedirrespective of prostate size, and was not associatedwith increased incidence of acute urinary retention(AUR) [Roehrborn et al., 2008].

Thus both the IR and ER forms of tolterodine have awell-documented effect in OAB/DO (Table 2), and arewell tolerated.

5. DARIFENACIN HYDROBROMIDE

Darifenacin is a tertiary amine with moderatelipophilicity, well absorbed from the gastrointestinal tractafter oral administration, and extensively metabolisedin the liver by the cytochrome P450 isoforms CYP3A4and CYP2D6, the latter saturating within thetherapeutic range [Skerjanec 2006]. UK-148,993, UK-73,689, and UK-88862 are the three main circulatingdarifenacin metabolites of which only UK-148,993 issaid to have significant anti-muscarinic activity.However, available information suggests that variousmetabolites of darifenacin contribute little to its clinicaleffects [Michel and Hegde, 2006]. The metabolismof darifenacin by CYP3A4 suggests that co-administration of a potent inhibitor of this enzyme(e.g. ketoconazole) may lead to an increase in thecirculating concentration of darifenacin [Kerbusch etal., 2003].

Darifenacin is a relatively selective muscarinic M3receptor antagonist. In vitro, it is selective for humancloned muscarinic M3 receptors relative to M1, M2,M4 or M5 receptors. Theoretically, drugs with selectivityfor the M3 receptor can be expected to have clinicalefficacy in OAB/DO with reduction of the adverseevents related to the blockade of other muscarinicreceptor subtypes [Andersson, 2002]. However, theclinical efficacy and adverse effects of a drug aredependent not only on its profile of receptor affinity,but also on its pharmacokinetics, and on theimportance of muscarinic receptors for a given organfunction.

Darifenacin has been developed as a controlled-release formulation, which allows once-daily dosing.Recommended dosages are 7.5 and 15 mg per day.The clinical effectiveness of the drug has beendocumented in several RCTs [Haab et al., 2004;Cardozo and Dixon 2005; Steers et al., 2005; Chappleet al., 2005; Foote et al., 2005; Hill et al., 2006; Haabet al., 2006; Zinner et al., 2006, Chapple et al., 2007;Abrams et al., 2008, Chancellor et al., 2008; Dwyeret al., 2008; for reviews, see Guay, 2005; Zinner,2007; Novara et al., 2008; Chapple et al., 2008]. Haab

et al. [2004] reported a multicentre, double-blind,placebo-controlled, parallel-group study which enrolled561 patients (19−88 years; 85% female) with OABsymptoms for more than 6 months, and includedsome patients with prior exposure to antimuscarinicagents. After washout and a 2-week placebo run-in,patients were randomised (1:4:2:3) to once-daily oraldarifenacin controlled-release tablets: 3.75 mg (n=53),7.5 mg (n=229) or 15 mg (n=115) or matchingplacebo (n=164) for 12 weeks. Patients recordeddaily incontinence episodes, micturition frequency,bladder capacity (mean volume voided), frequencyof urgency, severity of urgency, incontinence episodesresulting in change of clothing or pads and nocturnalawakenings due to OAB using an electronic diaryduring weeks 2, 6 and 12 (directly preceding clinicvisits). Tolerability data were evaluated from adverseevent reports. Darifenacin 7.5 mg and 15 mg had arapid onset of effect, with significant improvementcompared with placebo being seen for mostparameters at the first clinic visit (week 2). Darifenacin7.5 mg and 15 mg, respectively, was significantlysuperior to placebo for (median) improvements inmicturition frequency (7.5 mg: -1.6; 15 mg: -1.7;placebo -0.8, frequency of urgency per day (-2.0; -2.0;-0.9), and number of incontinence episodes leadingto a change in clothing or pads (-4.0; -4.7; -2.0). Therewas no significant reduction in nocturnal awakeningsdue to OAB.The most common adverse events weremild-to-moderate dry mouth and constipation with aCNS and cardiac safety profile comparable to placebo.No patients withdrew from the study as a result of drymouth and discontinuation related to constipation wasrare (0.6% placebo versus 0.9% darifenacin).

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In a dose titration study on 395 OAB patients,darifenacin, allowing individualized dosing (7.5 or 15mg), was found to be effective and well-tolerated[Steers et al., 2005]. A 2-year open label extensionstudy of these investigations [i.e., Haab et al., 2004;Steers et al., 2005], confirmed a favorable efficacy,tolerability and safety profile [Haab et al., 2006].

A review of the pooled darifenacin data from the threephase III, multicentre, double blind clinical trials inpatients with OAB was reported by Chapple et al.[2005] After a 4-week washout/run-in period, 1,059adults (85% female) with symptoms of OAB (urgencyincontinence, urgency and frequency) for at least sixmonths were randomized to once-daily oral treatmentwith darifenacin: 7.5 mg (n = 337) or 15 mg (n =334) or matching placebo (n = 388) for 12 weeks.Efficacy was evaluated using electronic patient diariesthat recorded incontinence episodes (including thoseresulting in a change of clothing or pads), frequencyand severity of urgency, micturition frequency, andbladder capacity (volume voided). Safety wasevaluated by analysis of treatment-related adverseevents, withdrawal rates and laboratory tests. Relativeto baseline, 12 weeks of treatment with darifenacinresulted in a dose-related significant reduction inmedian number of incontinence episodes per week(7.5 mg, –8.8 [–68.4%; placebo -54%, P<004]; 15mg, –10.6 [–76.8%; placebo 58%, p<0.001]. Significantdecreases in the frequency and severity of urgency,micturition frequency, and number of incontinenceepisodes resulting in a change of clothing or padswere also apparent, along with an increase in bladdercapacity. Darifenacin was well tolerated. The mostcommon treatment-related adverse events were drymouth and constipation, although together theseresulted in few discontinuations (darifenacin 7.5 mg0.6% of patients; darifenacin 15 mg 2.1%; placebo0.3%). The incidence of CNS and cardiovascularadverse events were comparable to placebo. Theresults were confirmed in other RCTs, including alsoa pooled analysis of three phase III studies in olderpatients (>65 years), showing that darifenacin (7.5and 15 mg) had an excellent efficacy, tolerability andsafety profile [Foote et al., 2005, Zinner et al., 2005;Hill et al. 2006].

One of the most noticeable clinical effects ofantimuscarinics is their ability to reduce urgency andallow patients to postpone micturition. A study wasconducted to assess the effect of darifenacin, on the‘warning time’ associated with urinary urgency. Thiswas a multicenter, randomized, double-blind, placebo-controlled study consisting of 2 weeks’ washout, 2weeks’ medication-free run-in and a 2-week treatmentphase [Cardozo and Dixon, 2005]. Warning time wasdefined as the time from the first sensation of urgencyto voluntary micturition or incontinence and wasrecorded via an electronic event recorder at baseline(visit 3) and study end (visit 4) during a 6-hour clinic-

based monitoring period, with the subject instructedto delay micturition for as long as possible. Duringeach monitoring period, up to three urgency-voidcycles were recorded. Of the 72 subjects who enteredthe study, 67 had warning time data recorded at bothbaseline and study end and were included in theprimary efficacy analysis (32 on darifenacin, 35 onplacebo). Darifenacin treatment resulted in a significant(p<0.004) increase in mean warning time with amedian increase of 4.3 minutes compared with placebo(darifenacin group from 4.4 to 1.8 minutes; placebofrom 7.0 to -1.0 minutes). Overall, 47% of darifenacin-treated subjects compared with 20% receiving placeboachieved a ≥30% increase in mean warning time.There were methodological problems associated withthis study; it utilized a dose of 30 mg (higher than thedose recommended for clinical use), the treatmentperiod was short, it was conducted in a clinical-centredenvironment, the methodology carried with it asignificant potential training effect, and the placebogroup had higher baseline values than the treatmentgroup. In another warning time study [Zinner et al.,2006] on 445 OAB patients, darifenacin treatment(15 mg) resulted in numerical increases in warningtime, however, these were not significant comparedto placebo.

Further studies have demonstrated that darifenacintreatment is associated with clinically relevantimprovements on health related quality of life (HRQoL)in patients with OAB [Abrams et al., 2008], and suchimprovements were sustained as shown in a two-year extension study [Dwyer et al., 2008]. It wasshown that neither the positive effects on micturitionvariables, nor on HRQoL produced by darifenacin(7.5 and 15 mg) were further enhanced by abehavioural modification programme including timedvoiding, dietary modifications and Kegel exercises[Chancellor et al., 2008].

Several studies have been devoted to study possibleeffect on cognition by darifenacin. Neither in healthyvolunteers (19-44 years) and healthy subjects (>60years), nor in volunteers 65 years or older, could anyeffect of darifenacin (3.75-15mg daily) bedemonstrated, compared to placebo [Kay and Wesnes,2005; Lipton et al., Kay et al., 2006; Kay and Ebinger2008].

To study whether darifenacin had any effect on QT/QTcintervals [Serra et al., 2005] performed a 7-day,randomized, parallel-group study (n = 188) in healthyvolunteers receiving once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg)doses, alongside controls receiving placebo ormoxifloxacin (positive control, 400 mg) once daily. Nosignificant increase in QTcF interval could bedemonstrated compared with placebo. Mean changesfrom baseline at pharmacokinetic Tmax versus placebowere –0.4 and –2.2 milliseconds in the darifenacin15mg and 75 mg groups, respectively, compared with

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+11.6 milliseconds in the moxifloxacin group (P < .01).The conclusion was that darifenacin does not prolongthe QT/QTc interval.

Darifenacin 15 mg per day given to healthy volunteersdid not change heart rate significantly compared toplacebo [Olshansky et al., 2008].

Darifenacin has a well-documented beneficial effectin OAB/DO (Table 2), and tolerability and safety seemsacceptable.

6. SOLIFENACIN SUCCINATE

Solifenacin succinate (YM905) is a tertiary amine andwell absorbed from the gastrointestinal tract (absolutebioavailability 90%). The mean terminal half-life is 45-68 hours [Kuipers et al., 2002; Smulders et al., 2002;2004]. It undergoes hepatic metabolism involving thecytochrome P450 enzyme system (CYP3A4). Insubjects who received a single oral dose of 10 mgsolifenacin on day 7 of a 20-day regimen ofketoconazole administration (200 mg) Cmax andAUC0-inf were increased by only approximately 40%and 56%, respectively [Swart et al., 2006]. Solifenacinhas a modest selectivity for M3 over M2 (and M1)receptors [Abrams and Andersson, 2007].

Two large-scale phase 2 trials with parallel designs,comprising men and women, were performed [Chappleet al., 2004a, Smith et al., 2002]. The first dose-rangingstudy evaluated solifenacin 2.5 mg, 5 mg, 10 mg, and20 mg and tolterodine (2 mg twice daily) in amultinational placebo-controlled study of 225 patientswith urodynamically confirmed DO [Chapple et al.,2004a]. Patients received treatment for 4 weeksfollowed by 2 weeks of follow-up. Inclusion criteriafor this and subsequent phase 3 studies of patientswith OAB included at least 8 micturitions per 24 hoursand either one episode of incontinence or one episodeof urgency daily as recorded in 3-day micturitiondiaries. Micturition frequency, the primary efficacyvariable, was statistically significantly reduced inpatients taking solifenacin 5 mg (-2.21), 10 mg (-2.47),and 20 mg (-2.75), but not in patients receiving placebo(-1.03) or tolterodine (-1.79). This effect was rapidwith most of the effect observed at the earliestassessment visit, 2 weeks after treatment initiation.In addition, there was numerically greater reductionsin episodes of urgency and incontinence whencompared with placebo. Study discontinuations dueto adverse events were similar across treatmentgroups, albeit highest in the 20-mg solifenacin group.As the 5 mg and 10 mg doses caused lower rates ofdry mouth than tolterodine, and superior efficacyoutcomes relative to placebo, these dosing strengthswere selected for further evaluation in large-scalephase 3 studies.

The second dose-ranging study of solifenacin 2.5 mgto 20 mg was carried out in the United States (USA)[Smith et al., 2002]. This trial included 261 evaluable

men and women receiving solifenacin or placebo for4 weeks followed by a 2-week follow-up period.Micturition frequency was statistically significantlyreduced relative to placebo in patients receiving 10mg and 20 mg solifenacin. The number of micturitionsper 24 hours showed reductions by day 7 andcontinued to decrease through day 28; day 7 was theearliest time point tested. Efficacy was demonstratedat this time. The 5 mg, 10 mg, and 20 mg dosinggroups experienced significant increases in volumevoided; the 10 mg solifenacin dose was associatedwith significant reductions in episodes of incontinence.

In one of the early RCTs, a total of 1077 patients wererandomized to 5 mg solifenacin, 10 mg solifenacin,tolterodine (2 mg twice daily), or placebo [Chapple etal., 2004b]. It should be noted that this study waspowered only to compare active treatments to placebo.Compared with placebo (-8%), mean micturitions/24h were significantly reduced with solifenacin 10 mg(20%), solifenacin 5 mg (17%), and tolterodine (15%).Solifenacin was well tolerated, with few patientsdiscontinuing treatment. Incidences of dry mouth were4.9% with placebo, 14.0% with solifenacin 5 mg,21.3% with solifenacin 10 mg, and 18.6% withtolterodine 2 mg twice daily.

Cardozo et al. [2004] randomized 911 patients to 12-week once daily treatment with solifenacin 5 mg,solifenacin 10 mg or placebo. The primary efficacyvariable was change from baseline to study end pointin mean number of micturitions per 24 hours.Secondary efficacy variables included changes frombaseline in mean number of urgency, nocturia andincontinence episodes per 24 hours, and mean volumevoided per micturition. Compared with changesobtained with placebo (-1.6), the number of micturitionsper 24 hours was statistically significantly decreasedwith solifenacin 5 mg (-2.37) and 10 mg (-2.81). Astatistically significant decrease was observed in thenumber of all incontinence episodes with bothsolifenacin doses (5 mg: -1.63, 61%; 10 mg: -1.57,52%), but not with placebo (-1.25, 28%). Of patientsreporting incontinence at baseline, 50% achievedcontinence after treatment with solifenacin (based ona 3-day micturition diary, placebo responses not given).Episodes of nocturia were statistically significantlydecreased in patients treated with solifenacin 10 mgversus placebo. Episodes of urgency and meanvolume voided per micturition were statisticallysignificantly reduced with solifenacin 5 mg and 10mg. Treatment with solifenacin was well tolerated.Dry mouth, mostly mild in severity, was reported in7.7% of patients receiving solifenacin 5 mg and 23%receiving solifenacin 10 mg (vs 2.3% with placebo).A 40-week follow up of these studies [i.e., Chapple etal., 2004b and Cardozo et al., 2004] demonstrated thatthe favourable profile, both in terms of efficacy andtolerability was maintained over the study period [Haabet al., 2005].

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The STAR trial [Chapple et al., 2005; 2007] was aprospective, double blind, double-dummy, two-arm,parallel-group, 12-week study conducted to comparethe efficacy and safety of solifenacin 5 or 10 mg andTOLT-ER 4 mg once daily in OAB patients. The primaryeffect variable was micturition frequency. After 4 weeksof treatment patients had the option to request a doseincrease, but were dummied throughout as approvedproduct labelling only allowed an increase for thoseon solifenacin. The results showed that solifenacin, witha flexible dosing regimen, was “non-inferior” totolterodine concerning the primary effect variable,micturition freqency. However, solifenacin showedsignificant greater efficacy to tolterodine in decreasingurgency episodes (-2.85 vs -2.42), incontinence (-1.60 vs -.83), urgency incontinence (-1.42 vs -0.83),and pad usage (-1.72 vs -1.19). More solifenacintreated patients became continent by study endpoint(59 vs 49%) and reported improvements in perceptionof bladder condition (1.51 vs -1.33) assessments.However, this was accompanied by an adverse eventincidence which was greater with solifenacin thanwith tolterodine. Dry mouth and constipation (mild +moderate + severe) were the most common(solifenacin 30% and 6.4%, tolterodine 23% and2.5%). The majority of side effects were mild tomoderate in nature, and discontinuations werecomparable and low (5.9 and 7.3%) in both groups.

A number of studies and reviews have furtherdocumented the effects of solifenacin [Cardozo et al.,2006; Chapple et al., 2006; 2007; Maniscalco et al.,2006, see also Chapple et al., 2008; Novara et al.,2008]. In a pooled analysis of four RCTs, Abrams andSwift (2005) demonstrated positive effects on urgency,frequency and nocturia symptoms in OAB dry patients.In an analysis of four phase III clinical trials, Brubakerand FitzGerald [2007] confirmed a significant effect ofsolifenacin 5 and 10 mg on nocturia in patients withOAB (reductions of nocturia episodes with 5 mg: -0.6, p<0.025; with 10 mg: -0.6, p<0.001vs placebo: -0,4) but without nocturnal polyuria.

Kelleher et al. [2006] and Staskin and Te [2006]presented data showing efficacy in patients with mixedincontinence. A pooled analysis of four studiesconfirmed the efficacy and tolerability of solifenacin 5and 10 mg in elderly (> 65 years) patients, and alsoshowed a high level of persistence in a 40 weekextension trial [Wagg et al., 2005]. Improvement of QoLby solifenacin treatment has been documented inseveral studies [Kelleher et al., 2005; Garely et al.,2006].

In female volunteers, aged 19 to 79 years, the effectof 10 mg and 30 mg solifenacin on the QT interval wasevaluated at the time of peak solifenacin plasmaconcentration in a multi-dose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400mg) trial. The QT interval prolonging effect appeared

greater for the 30 mg (8 msec, 4, 13: 90%CI) comparedto the 10 mg (2 msec, -3, 6) dose of solifenacin.Although the effect of the highest solifenacin dose(three times the maximum therapeutic dose) studieddid not appear as large as that of the positive controlmoxifloxacin at its therapeutic dose, the confidenceintervals overlapped. This study was not designed todraw direct statistical conclusions between the drugsor the dose levels.

Michel et al. [2008] studied cardiovascular safety andoverall tolerability of solifenacin in routine clinical usein a 12-week, open-label, post-marketing surveillancestudy. They concluded that “in real-life conditions, i.e.with inclusion of large numbers of patients withcardiovascular co-morbidities and takingcomedications, therapeutically effective doses ofsolifenacin did not increase heart rate or bloodpressure”.

Solifenacin has a well-documented beneficial effectin OAB/DO (Table 2), and the adverse event profileseems acceptable.

7. FESOTERODINE FUMARATE

Fesoterodine functions as an orally active prodrugthat is converted to the active metabolite 5-hydroxymethyltolterodine (5-HMT) by non-specificesterases [Michel, 2008]. This compound, which is ischemically identical to the 5-hydroxy metabolite oftolterodine, is a non-subtype selective muscarinicreceptor antagonist [Ney et al., 2008]. All of the effectsof fesoterodine in man are thought to be mediated via5-HMT, since the parent compound remainsundetectable upon oral dosing. 5-HMT is metabolizedin the liver, but a significant part of 5-HMT is excretedrenally without additional metabolism. Since the renalclearance of 5-HMT is about 250 mL/min, with >15%of the administered fesoterodine dose excreted asunchanged 5-HM, this raises the possibility that 5-HMT also could work from the luminal side of thebladder [Michel, 2008].

Fesoterodine is indicated for use at doses of 4 and 8mg once daily. In clinical studies both doses offesoterodine were consistently superior to placebo inimproving the symptoms of OAB [Chapple et al., 2007;Nitti et al., 2007], with 8 mg/day having significantlygreater effects than 4 mg/day [Khullar et al., 2008].Analysis of pooled data on QoL, using King´s HealthQuestionnaire and ICI Questionnaire-short Form,showed that both doses of the drug caused asignificant improvement of QoL. Compared to TOLT-ER (4 mg), fesoterodine (8 mg) had statisticallysignificant advantages for improving incontinenceepisodes, severe urgency with incontinence, meanvoided volumes and number of continent days a week[Chapple et al., 2008; Khullar et al., 2008]. Adverseevents were characteristic for an antimuscarinic, drymouth being the most frequently reported – it was

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was rated as mild to moderate in most cases. In onephase III study it was seen in 7%, 16% and 36% ofpatients receiving placebo, 4 and 8 mg/d fesoterodine,respectively [Nitti et al., 2007], whereas in the anotherphase III study it was 7.1%, 21.7% and 33.8% in thesame groups (16.9% for 4 mg/day TOLT-ER) [Chappleet al., 2007].

Kelleher et al. [2008] evaluated the effect offesoterodine on HRQoL in patients with OABsyndrome. Pooled data from two randomized placebo-controlled phase III studies were analysed. Eligiblepatients were randomized to placebo or fesoterodine4 or 8 mg for 12 weeks; one trial also includedtolterodine extended release (tolterodine-ER) 4 mg.By the end of treatment, all active-treatment groupshad significantly improved HRQoL compared withthose on placebo.

A study on possible effects on QT-intervals has beenperformed [Michel, 2008]. This included parallel groupsof 64-68 subjects each who were treated for 3 dayswith 4 mg/d fesoterodine, the highly supratherapeuticdose of 28 mg/d fesoterodine, the active controlmoxifloxacin 400 mg/day or placebo. Both the standarddose of 4 mg/day and the highly supratherapeuticdose of 28 mg/d did not provide any evidence of QT-prolongation (e.g., QTc for 28 mg/day from 404.5 ± 16.7to 400.1 ± 14.0 ms, delta: -5.0 ± 7.9 ms).

Fesoterodine has a well-documented beneficial effectin OAB (Table 2), and the adverse event profile seemsacceptable.

1. CALCIUM ANTAGONISTS

Calcium channels play an important role in theregulation of free intracellular calcium concentrationsand thereby contribute to the regulation of smoothmuscle tone. Two major groups of calcium channelsinclude the voltage-gated [Caterall et al., 2003] andthe store-operated channels (Leung et al., 2008).While both can contribute to the maintenance ofsmooth tone in general, store-operated calciumchannels apparently contribute only to a limited if anyextent to the regulation of bladder smooth muscletone [Schneider et al., 2004 a; b]. On the other hand,various types of voltage-operated calcium channelshave been implicated in the regulation of bladdersmooth muscle tone including including Q-type [Frewand Lundy, 1995] and L-type channels [Wuest et al.,2007]. The latter appears to be of particular importanceas inhibitors of L-type channels have repeatedly beenshown to inhibit bladder contraction in vitro with tissuefrom multiple mammalian species, including humans[Frazier et al., 2008]. However, the relative importance

of L-type channels may be somewhat less in humansthan in other mammalian species [Wuest et al., 2007].In confirmation of the role of L-type calcium channels,it has been shown that knock-out mice lacking a crucialsubunit of this channel exhibit a markedly impairedbladder contractility [Wegener et al., 2004].

While these in vitro data suggest a possible role forcalcium channel inhibitors, particularly those of L-type channels, in the treatment of DO andincontinence, only limited clinical studies are availablein this regard. One urodynamic study compared theeffects of intravesical instillation of the calcium channelinhibitor verapamil, the muscarinic receptor antagonistsoxybutynin and trospium and placebo to patients withurgency or urgency incontinence. While the twomuscarinic receptor antagonists significantly increasedbladder capacity, verapamil treatment was notassociated with relevant changes in bladder function[Fröhlich et al., 1998]. In a clinical study of limitedsize the calcium channel inhibitor nimodipine (30 mgper day) did not significantly improve the number ofincontinence episodes as compared to placebo [Naglieet al., 2002]. Larger studies with clinical endpointsrelated to effects of calcium channel inhibitors havenot been reported in incontinent patients (based upona Medline search using the MeSH terms “calciumchannel blockers” and “urinary incontinence”).Moreover, it should be noted that despite a long-standing and wide-spread use of calcium channelinhibitors in the treatment of cardiovascular disease,there are no major reports on impaired bladdercontractility as a side effect of such treatment. Thereasons for the discrepancy between the promisingin vitro and the lack of clinical data are not fully clear,but it may relate to pharmacokinetic properties of thecurrently used drugs which may insufficiently eitherreach or penetrate bladder tissue in therapeuticallyadministered doses. At present, there is no clinicalevidence to support a possible use of calcium channelinhibitors in the treatment of bladder dysfunction (Table2).

2. POTASSIUM CHANNEL OPENERS

In a similar fashion to calcium channels, potassiumchannels also contribute to the membrane potentialof smooth muscle cells and hence to the regulationof smooth muscle tone. Numerous types of potassiumchannels exist [Gutman et al., 2003]. With regard tobladder function, ATP-dependent (KATP) and bigcalcium-activated (BKCa) channels have been studiedmost intensively. The BKCa channels also appear tobe important physiologically as their activation cancause hyperpolarization of bladder smooth musclecells and by this mechanism they can contribute to therelaxation of bladder smooth muscle by, e.g.,β-adrenoceptor agonists [Frazier et al., 2008]. Openersof both KATP [Howe et al., 1995; Hu et al., 1997;Martin et al., 1997] and BKCa channels [Hu et al.,

II. DRUGS ACTING ON MEMBRANECHANNELS

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1997; Sheldon et al., 1997] have been shown to inducebladder smooth muscle relaxation in variousmammalian species, but the density of some types ofpotassium channels may differ markedly betweenspecies. Some potassium channel openers have alsobeen shown to suppress non-voiding detrusorcontractions in vivo in animal models of DO [Howe etal., 1995; Martin et al., 1997; Tanaka et al., 2003] andthis also includes activators of the KCNQ type ofpotassium channels [Streng et al., 2004]. Althoughpotassium channel openers are believed to mainlyact directly on smooth muscle cells [Gopalakrishnanand Shieh, 2004], they may also at least in part affectbladder function by modulating the activity of afferentneurones [Tanaka et al., 2003].

While the above data demonstrate the potential ofpotassium channel openers to inhibit non-voidingdetrusor contractions, these channels are expressednot only in bladder, but also e.g. in vascular smoothmuscle. Therefore, potassium channel openers mayalso affect cardiovascular function, and in effectivedoses may considerably lower blood pressure [Howeet al., 1995; Shieh et al., 2007]. While somecompounds of this class have a certain degree ofselectivity for the bladder as compared to thecardiovascular system, it remains unclear whetherthe degree of selectivity offers a sufficiently largetherapeutic window for clinical use. This considerationhas led to a considerable hesitancy to study potassiumchannel openers in OAB patients. Nevertheless, onerandomized, placebo-controlled clinical study on theKATP opener ZD0947 has been reported [Chapple et

al., 2006]. While ZD0947 at the chosen dose did notlower blood pressure or cause adverse events typicalfor a vasodilating drug, it also failed to achievesuperiority relative to placebo for the treatment ofOAB symptoms. Therefore, despite promisingpreclinical efficacy data, potassium channel openersat present are not a therapeutic option and may neverbecome one due to a lack of selectivity for bladder overcardiovascular tissues (Table 2).

Some drugs used to block DO have been shown tohave more than one mechanism of action. They allhave a more or less pronounced antimuscarinic effectand, in addition, an often poorly defined “direct” actionon bladder muscle. For several of these drugs, theantimuscarinic effects can be demonstrated at muchlower drug concentrations than the direct action, whichmay involve blockade of voltage operated Ca2+

channels. Most probably, the clinical effects of thesedrugs can be explained mainly by an antimuscarinicaction. Among the drugs with mixed actions wasterodiline, which was withdrawn from the marketbecause it was suspected to cause polymorphicventricular tachycardia (torsade de pointes) in somepatients [Connolly et al., 1991; Stewart et al., 1992].

1. OXYBUTYNIN CHLORIDE

Oxybutynin is a tertiary amine that is well absorbed,and undergoes extensive upper gastrointestinal andfirst-pass hepatic metabolism via the cytochrome P-450 system (CYP3A4) into multiple metabolites. Theprimary metabolite, N-desethyloxybutynin (DEO) haspharmacological properties similar to the parentcompound [Waldeck et al., 1997], but occurs in muchhigher concentrations after oral administration [Hugheset al., 1992]. It has been implicated as the major causeof the troublesome side effect of dry mouth associatedwith the administration of oxybutynin. It seemsreasonable to assume that the effect of oral oxybutyninto a large extent is exerted by the metabolite. Theoccurrence of an active metabolite may also explainthe lack of correlation between plasma concentrationof oxybutynin itself and side effects in geriatric patientsreported by Ouslander et al. [1988]. The plasma half-life of the oxybutynin is approximately 2 hours, but withwide interindividual variation [Hughes et al., 1992;Douchamps et al, 1988].

Oxybutynin has several pharmacological effects invitro, some of which seem difficult to relate to itseffectiveness in the treatment of DO. It has both anantimuscarinic and a direct muscle relaxant effect,and, in addition, local anesthetic actions. The lattereffect may be of importance when the drug isadministered intravesically, but probably plays no rolewhen it is given orally. In vitro, oxybutynin was 500times weaker as a smooth muscle relaxant than asan antimuscarinic agent [Kachur et al., 1988]. Mostprobably, when given systemically, oxybutynin actsmainly as an antimuscarinic drug. Oxybutynin has ahigh affinity for muscarinic receptors in human bladdertissue and effectively blocks carbachol-inducedcontractions [Waldeck et al., 1997; Nilvebrant et al.,1988]. The drug was shown to have slightly higheraffinity for muscarinic M1 and M3 receptors than forM2 receptors [Nilvebrant et al., 1986; Norhona-Blobet al., 1991], but the clinical significance of this isunclear.

The immediate release (IR) form of oxybutynin (OXY-IR) is recognized for its efficacy and most of the neweranti-muscarinic agents have been compared to it onceefficacy over placebo has been determined. In general,the new formulations of oxybutynin and other anti-muscarinic agents offer patients efficacy roughlyequivalent to that of OXY-IR, and the advantage of thenewer formulations lies in improved dosing schedulesand side-effect profile [Appell et al., 2001; Diokno etal., 2003; Dmochowski et al., 2002]. An extendedrelease oxybutynin (OXY-ER) once daily oralformulation and an oxybutynin transdermal deliverysystem (OXY-TDS) are available. OXY-TDS offers atwice-weekly dosing regimen and the potential forimproved patient compliance and tolerability.

Available formulations of oybutynin were overviewedby McCrery and Appell [2006].

III. DRUGS WITH “MIXED” ACTION

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a) Immediate-release oxybutynin (OXY-IR)

Several controlled studies have have shown that OXY-IR is effective in controlling DO, including neurogenicDO [Yarker et al., 1995; Andersson and Chapple,2001]. The recommended oral dose of the IR form is5 mg three times daily or four times daily, even if lowerdoses have been used. Thüroff et al. [1998]summarized 15 randomized controlled studies on atotal of 476 patients treated with oxybutynin. Themean decrease in incontinence was recorded as 52%and the mean reduction in frequency per 24 h was 33%(data on placebo not presented). The overall”subjective improvement” rate was reported as 74 %(range 61% - 100%). The mean percent of patientsreporting an adverse effect was 70 (range 17% -93%). Oxybutynin, 7.5 to 15 mg/day, significantlyimproved quality of life of patients suffering fromoveractive bladder in a large open multicenter trial. Inthis study, patients´ compliance was 97% and sideeffects, mainly dry mouth, were reported by only 8%of the patients [Amaranco et al., 1998]. In nursinghome residents (n=75), Ouslander et al. [1995] foundthat oxybutynin did not add to the clinical effectivenessof prompted voiding in a placebo-controlled, doubleblind, cross-over trial. On the other hand, in anothercontrolled trial in elderly subjects (n=57), oxybutyninwith bladder training was found to be superior tobladder training alone [Szonyi et al., 1995].

Several open studies in patients with spinal cordinjuries have suggested that oxybutynin, given orallyor intravesically, can be of therapeutic benefit [Szolleret al., 1996; Kim et al., 1996].

The therapeutic effect of OXY-IR on DO is associatedwith a high incidence of side effects (up to 80% withoral administration). These are typically antimuscarinicin nature (dry mouth, constipation, drowsiness, blurredvision) and are often dose-limiting [Baigrie et al., 1988;Jonville et al., 1992]. The effects on the electro-cardiogram of oxybutynin were studied in elderlypatients with urinary incontinence [Hussain et al.,1998]; no changes were found. It cannot be excludedthat the commonly recommended dose 5 mg x 3 isunnecessarily high in some patients, and that a startingdose of 2.5 mg x 2 with following dose-titration wouldreduce the number of adverse effects [Amarenco etal., 1998].

b) Extended release oxybutynin (OXY-ER)

This formulation was developed to decrease livermetabolite formation of desethyloxybutynin (DEO)with the presumption that it would result in decreasedside effects, especially dry mouth, and improve patientcompliance with remaining on oxybutynin therapy.The formulation utilizes an osmotic system to releasethe drug at a controlled rate over 24 hours distallyprimarily into the large intestine where absorption isnot subject to first-pass metabolism in the liver. This

reduction in metabolism is meant to improve the rateof dry mouth complaints when compared to OXY-IR.DEO is still formed through the hepatic cytochromeP-450 enzymes, but clinical trials have indeeddemonstrated improved dry mouth rates comparedwith OXY-IR [Appell et al., 2003]. Salivary outputstudies have also been interesting. Two hours afteradministration of OXY-IR or TOLT-IR, salivaryproduction decreased markedly and then graduallyreturned to normal. With OXY-ER, however, salivaryoutput was maintained at predose levels throughoutthe day [Chancellor et al., 2001].

The effects of OXY-ER have been well documented[Siddiqui et al., 2004]. In the OBJECT study [Appellet al., 2001], the efficacy and tolerability of 10 mgOXY-ER was compared to a twice daily 2 mg dose ofTOLT-IR. OXY-ER was statistically more effectivethan the TOLT-IR in weekly urgency incontinenceepisodes (OXY-ER from 25.6% to 6.1%; TOLT-IR24.1% to 7.8%), total incontinence (OXY-ER from28.6% to 7.1%; TOLT-IR 27.0% to 9.3%), andfrequency (OXY-ER from 91.8% to 67.1%; TOLT-IR91.6% to 71.5%) and both medications were equallywell tolerated. The basic study was repeated as theOPERA study [Diokno et al., 2003] with the differencethat this study was a direct comparison of the twoextended-release forms, OXY-ER (10 mg) and TOLT-ER (4 mg) and the results were quite different. In thisstudy there was no significant difference in efficacy forthe primary endpoint of urgency incontinence, however,TOLT-ER had a statistically lower incidence of drymouth. OXY-ER was only statistically better at 10 mgthan TOLT-ER 4 mg in the reduction of the rate ofurinary frequency. These studies made it clear that incomparative studies IR entities of one drug shouldnot be compared with ER entities of the other.

Greater reductions in urgency and total incontinencehave been reported in patients treated in dose-escalation studies with OXY-ER. In two randomizedstudies, the efficacy and tolerability of OXY-ER werecompared with OXY-IR. In the 1999 study [Andersonet al., 1999], 105 patients with urgency or mixedincontinence were randomized to receive 5-30 mgOXY-ER once daily or 5 mg of OXY-IR 1-4 times/day.Dose titrations began at 5 mg and the dose wasincreased every 4-7 days until one of three endpointswas achieved. These were 1) the patient reported nourgency incontinence during the final two days of thedosing period; 2) the maximum tolerable dose wasreached; the maximum allowable dose (30 mg forOXY-ER or 20 mg for OXY-IR) was reached. Themean percentage reduction in weekly urgency and totalincontinence episodes was statistically similar betweenOXY-ER and OXY-IR but dry mouth was reportedstatistically more often with OXY-IR. In the 2000 study[Versi et al., 2000], 226 patients were randomizedbetween OXY-ER and OXY-IR with weekly incrementsof 5 mg daily up to 20 mg daily. As in the 1999 study,

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OXY-ER again achieved a >80% reduction in urgencyand total incontinence episodes and a significantpercentage of patients became dry. A negative aspectof these studies is that there were no naïve patientsincluded, as all patients were known responders tooxybutynin. Similar efficacy results have beenachieved, however, with OXY-ER in a treatment-naïvepopulation [Gleason et al., 1999].

In an RCT comparing different daily doses ofoxybutynin (5, 10 and 15 mg), Corcos et al. [2006]found a significant dose-response relationship forboth urgency incontinence episodes and dry mouth.The greatest satisfaction was with 15 mg oxybutynin/day.

c) Transdermal oxybutynin (OXY-TDS)

Transdermal delivery also alters oxybutyninmetabolism reducing DEO production to an evengreater extent than OXY-ER. A study [Davila et al.,2001] comparing OXY-TDS with OXY-IR demonstrateda statistically equivalent reduction in daily incontinentepisodes (from 7.3 to 2.3: 66% for OXY-TDS, and 7.4to 2.6: 72% for OXY-IR), but much less dry mouth(38% for OXY-TDS and 94% for OXY-IR). In anotherstudy [Dmochowski et al., 2002] the 3.9-mg daily dosepatch significantly (vs placebo) reduced the meannumber of daily incontinence episodes (from 4.7 to 1.9;placebo from 5.0 to 2.9), while reducing average dailyurinary frequency confirmed by an increased averagevoided volume (from 165 to 198 ml; placebo from 175to 182 ml). Furthermore, dry mouth rate was similarto placebo (7% vs 8.3%). In a third study [Dmochowskiet al., 2003] OXY-TDS was compared not only toplacebo but to TOLT-ER. Both drugs equivalently andsignificantly reduced daily incontinence episodes andincreased the average voided volume, but TOLT-ERwas associated with a significantly higher rate ofantimuscarinic adverse events. The primary adverseevent for OXY-TDS was application site reactionpruritis in 14% and erythema in 8.3% with nearly 9%feeling that the reactions were severe enough towithdraw from the study, despite the lack of systemicproblems.

The pharmacokinetics and adverse effect dynamicsof OXY-TDS (3.9 mg/day) and OXY-ER (10 mg/day)were compared in healthy subjects in a randomized,2-way crossover study [Appell et al., 2003]. Multipleblood and saliva samples were collected andpharmacokinetic parameters and total salivary outputwere assessed. OXY-TDS administration resulted ingreater systemic availability and minimal metabolismto DEO compared to OXY-ER which resulted in greatersalivary output in OXY-TDS patients and less drymouth symptomatology than when taking OXY-ER.

Dmochowski et al. [2005] analyzing the combinedresults of two RCTs concluded that transdermaloxybutynin was shown to be efficacious and well

tolerated. The most common systemic side effect wasdry mouth (7.0 % vs placebo 5.3%). Application siteerythema occurred in 7% and pruritus in 16.1 %. AlsoCartwright and Cardozo [2006], reviewing publishedand presented data concluded that transdermaloxybutynin has a good balance between efficacy andtolerability with a rate of systemic antimuscarinic sideeffects lower that with oral antimuscarinics – however,this benefit was offset by the rate of local skin reaction.Sahai et al. [2008] in a recent review largely confirmedthese conclusions.

d) Other administration forms

Rectal administration [Collas and Malone-Lee, 1997]was reported to have fewer adverse effects than theconventional tablets.

Administered intravesically, oxybutynin has in severalstudies been demonstrated to increase bladdercapacity and produce clinical improvement with fewside effects, both in neurogenic and in other types ofDO, and both in children and adults [Lose andNorgaard, 2001; Fader et al., 2007; George et al.,2007; Guerra et al., 2008], although adverse effectsmay occur [Kasabian et al., 1994; Palmer et al., 1997].

e) Effects on cognition

Several studies have documented the possibility thatoxybutynin may have negative effects on cognitivefunctions, particularly in the elderly population butalso in children [see, e.g., Kay et al., 2006; Klausneral Steers, 2007; Kay and Ebinger, 2008]. This factorshould be taken into consideration when prescribingthe drug.

Oxybutynin has a well-documented efficacy in thetreatment of OAB/DO (Table 2). Despite the adverseeffect profile, it is still an established therapeutic option.

2. PROPIVERINE HYDROCHLORIDE

Several aspects of the preclinical, pharmacokinetic,and clinical effects of propiverine have been reviewedby Madersbacher and Murz [2001]. The drug is rapidlyabsorbed (tmax 2 h), but has a high first passmetabolism, and its biological availability is about50%. Propiverine is an inducer of hepatic cytochromeP450 enzymes in rats in doses about 100-times abovethe therapeutic doses in man [Walter et al., 2003].Several active metabolites are formed whichquantitatively and qualitatively differ from the mothercompound [Haustein et al., 1988; Muller et al., 1993;Wuest et al., 2006; Zhu et al., 2008; Sugiyama et al.,2008]. Most probable these metabolites contribute tothe clinical effects of the drug, but their individualcontributions have not been clarified (Michel andHegde, 2006). The half-life of propiverine itself isabout 11-14 h. An extended release preparation wasshown to be effective [Junemann et al., 2006; May etal., 2008].

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Propiverine has combined antimuscarinic and calciumantagonistic actions [Haruno, 1992; Tokuno et al.,1993]. The importance of the calcium antagonisticcomponent for the drug´s clinical effects has not beenestablished. Propiverine has no selectivity formuscarinic receptor subtypes.

Propiverine has been shown to have beneficial effectsin patients with DO in several investigations. Thüroffet al [1998] collected 9 randomized studies on a totalof 230 patients, and found a 17% reduction inmicturitions per 24 hours, a 64 ml increase in bladdercapacity, and a 77% (range 33-80%) subjectiveimprovement. Side effects were found in 14 % (range8-42%). In patients with neurogenic DO, controlledclinical trials have demonstrated propiverine´ssuperiority over placebo [Stöhrer et al., 1999].Propiverine also increased bladder capacity anddecreased maximum detrusor contractions. Controlledtrials comparing propiverine, flavoxate and placebo[Wehnert et al., 1989], and propiverine, oxybutynin andplacebo [Wehnert et al., 1992; Madersbacher et al.,1999], have confirmed the efficacy of propiverine, andsuggested that the drug may have equal efficacy andfewer side effects than oxybutynin. In a comparativeRCT including 131 patients with neurogenic DO,propiverine and oxybutynin were compared [Stöhreret al., 2007]. The drugs were found to be equallyeffective in increasing bladder capacity and loweringbladder pressure. Propiverine caused a significantlylower frequency of dry mouth than oxybutynin.

Also in children and adolescents with neurogenic DO,propiverine was found to be effective [Schulte-Bauklohet al., 2006; Grigoleit et al., 2006], with a low incidencerate of adverse events: <1.5% [Grigoleit et al., 2006].

Madersbacher et al. [1999] compared the tolerabilityand efficacy of propiverine (15 mg three times daily)oxybutynin (5 mg twice daily) and placebo in 366patients with urgency and urgency incontinence in arandomized, double-blind placebo-controlled clinicaltrial. Urodynamic efficacy of propiverine was judgedsimilar to that of oxybutynin, but the incidence of drymouth and the severity of dry mouth were judged lesswith propiverine than with oxybutynin. Dorschner etal. [2000] investigated in a double-blind, multicentre,placebo-controlled, randomized study, the efficacyand cardiac safety of propiverine in 98 elderly patients(mean age 68 years), suffering from urgency, urgencyincontinence or mixed urgency-stress incontinence.After a 2-week placebo run-in period, the patientsreceived propiverine (15 mg three times daily) orplacebo (three times daily) for 4 weeks. Propiverinecaused a significant reduction of the micturitionfrequency (from 8.7 to 6.5) and a significant decreasein episodes of incontinence (from 0.9 to 0.3 per day).The incidence of adverse events was very low (2%dryness of the mouth under propiverine – 2 out of 49patients). Resting and ambulatory electrocardiogramsindicated no significant changes.

In a randomised, double-blind, multicentre clinicaltrial, patients with idiopathic DO were treated with 15mg propiverine twice daily or 2 mg TOLT-IR twicedaily over a period of 28 days [Junemann et al., 2005].The maximum cystometric capacity was determinedat baseline and after 4 weeks of therapy. The differenceof both values was used as the primary endpoint.Secondary endpoints were voided volume permicturition, evaluation of efficacy (by the investigator),tolerability, post void residual urine, and quality of life.It was found that the mean maximum cystometriccapacity increased significantly (p < 0.01) in bothgroups. The volume at first urgency and thefrequency/volume chart parameters also showedrelevant improvements during treatment. The mostcommon adverse event, dry mouth, occurred in 20patients in the propiverine group and in 19 patientsin the tolterodine group. The scores for the quality oflife improved comparably in both groups.

Abrams et al. [2006] compared the effects ofpropiverine and oxybutynin on ambulatory urodynamicmonitoring (AUM) parameters, safety, and tolerabilityin OAB patients. Patients (n=77) received two of thefollowing treatments during two 2-week periods:propiverine 20 mg once daily, propiverine 15 mg threetimes daily, oxybutynin 5 mg three times daily, andplacebo. They found that oxybutynin 15 mg was moreeffective than propiverine 20 mg in reducingsymptomatic and asymptomatic involuntary detrusorcontractions in ambulatory patients. Oxybutynin hada higher rate of dry mouth, and propiverine had amore pronounced effect on gastrointestinal, cardio-vascular, and visual function.

A randomized, double-blind, placebo-controlled trialwith parallel-group design in children aged 5–10 yr wasperformed by Marschall-Kehrel et al. [2008]. Of 171randomized children, 87 were treated with propiverineand 84 with placebo. Decrease in voiding frequencyper day was the primary efficacy parameter; secondaryendpoints included voided volume and incontinenceepisodes. There was a significant decrease in voidingfrequency episodes for propiverine versus placebo.Superiority could also be demonstrated for voidedvolume and incontinence episodes per day. Propiverinewas well-tolerated: 23% of side-effects were reportedfor propiverine and 20% for placebo.

Yamaguchi et al. [2008] performed a multicentre, 12-week, double-blind phase III trial in Japanese men andwomen with OAB (1593 patients were randomizedand 1584 were treated), comparing solifenacin 5 or10 mg, propiverine 20 mg, and placebo. Changes atendpoint in number of voids/24 hours, urgency,incontinence, urgency incontinence and nocturiaepisodes, volume voided/void, restoration ofcontinence and quality of life (QoL) were examined.It was found that at endpoint, there were greaterreductions in mean (SD) voids/24 hours with all drugregimens than with placebo. All active treatments

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improved the volume voided and QoL vs placebo;solifenacin 10 mg reduced nocturia episodes andsignificantly improved urgency episodes and volumevoided vs propiverine 20 mg, and solifenacin 5 mgcaused less dry mouth. Solifenacin 10 mg causedmore dry mouth and constipation than propiverine 20 mg.

Propiverine has a documented beneficial effect in thetreatment of OAB/DO (Table 2), and seems to havean acceptable side effect profile.

3. FLAVOXATE HYDROCHLORIDE

Flavoxate is well absorbed, and oral bioavailabilityappeared to be close to 100% [Guay, 2003].The drugis extensively metabolized and plasma half-life wasfound to be 3.5 h [Sheu et al., 2001]. Its mainmetabolite (3-methylflavone-8-carboxylic acid, MFCA)has been shown to have low pharmacological activity[Cazzulani et al., 1988; Caine et al., 1991]. The mainmechanism of flavoxate’s effect on smooth musclehas not been established. The drug has been foundto possess a moderate calcium antagonistic activity,to have the ability to inhibit phosphodiesterases, andto have local anesthetic properties; no antimuscariniceffect was found [Guarneri et al., 1994]. Uckert et al.[2000], on the other hand, found that in strips of humanbladder, the potency of flavoxate to reverse contractioninduced by muscarinic receptor stimulation and byelectrical field stimulation was comparable, It hasbeen suggested that pertussis toxin-sensitive G-proteins in the brain are involved in the flavoxate-induced suppression of the micturition reflex, sinceintracerebroventricularly or intrathecally administeredflavoxate abolished isovolumetric rhytmic bladdercontractions in anesthetized rats [Oka et al., 1996].

The clinical effects of flavoxate in patients with DO andfrequency, urgency and incontinence have beenstudied in both open and controlled investigations,but with varying rates of success [Ruffman, 1988].Stanton [1973] compared emepronium bromide andflavoxate in a double-blind, cross-over study of patientswith detrusor overactivity and reported improvementrates of 83% and 66% after flavoxate or emeproniumbromide, respectively, both administered as 200 mg3 times daily. In another double-blind, cross-over studycomparing flavoxate 1200 mg/day with that ofoxybutynin 15 mg daily in 41 women with idiopathicmotor or sensory urgency, and utilising both clinicaland urodynamic criteria, Milani et al. [1993] foundboth drugs effective. No difference in efficacy wasfound between them, but flavoxate had fewer andmilder side effects. Other investigators, comparingthe effects of flavoxate with those of placebo, have notbeen able to show any beneficial effect of flavoxateat dosages up to 400 mg three times daily [Briggs etal., 1980; Chapple et al., 1990; Dahm et al., 1995]. Ingeneral, few side effects have been reported duringtreatment with flavoxate. On the other hand its efficacy,

compared to other therapeutic alternatives, is not welldocumented (Table 2).

No RCTs seem to have been performed with flavoxateduring the last decade.

Even if it is well known that α-AR antagonists canameliorate lower urinary tract symptoms in men withBPE [Andersson et al., 2002], there are no controlledclinical trials showing that they are an effectivealternative in the treatment of OAB/DO in this patientcategory. In an open label study, Arnold [2001]evaluated the clinical and pressure-flow effects oftamsulosin 0.4 mg once daily in patients with lowerurinary tract symptoms (LUTS) caused by benignprostatic obstruction (BPO). He found that tamsulosinproduced a significant decrease in detrusor pressure,increase in flow rate and a symptomatic improvement.In a study where tamsulosin was given alone, ortogether with tolterodine, to patients with male LUTS,monotherapy with the drug was not effective [Kaplanet al., 2006]. An RCT, comprising 364 women withOAB, revealed no effect of tamsulosin vs placebo[Robinson et al., 2007]. On the other hand, voidingsymptoms in women with functional outflowobstruction, or LUTS, were successfully treated withan α1-AR antagonist [Kessler et al., 2006, Low et al.,

2008].

α1-AR antagonists have been used to treat patientswith neurogenic DO [Abrams et al., 2003]; however,the success has been moderate. Thus, there is noconvincing evidence that α1-AR antagonists areeffective in patients with storage symptoms. Althoughα1-AR antagonists may be effective in selected cases,convincing effects documented in RCTs are lacking(Table 2). In women, these drugs may produce stressincontinence [Dwyer and Teele, 1992].

In isolated human bladder, non-subtype selective β-AR agonists like isoprenaline have a pronouncedinhibitory effect, and administration of such drugs canincrease bladder capacity in man [Andersson, 1993].However, the β-ARs of the human bladder were shownto have functional characteristics typical of neitherβ1-, nor β2- ARs, since they could be blocked bypropranolol, but not by practolol or metoprolol (β1) orbutoxamine (β2) [Nergard et al., 1977; Larsen, 1979].On the other hand, early receptor binding studiesusing subtype selective ligands, suggested that theβ-ARs of the human detrusor are primarily of β2 subtype [Andersson 1993], and favourable effectson DO were reported in open studies with selective

V. ββ-ADRENOCEPTOR AGONISTS

IV. αα-ADRENOCEPTOR (AR)ANTAGONISTS

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β2-AR agonists such as terbutaline [Lindholm andLose, 1986]. In a double-blind investigation clenbuterol0.01 mg 3 times daily was shown to have a goodtherapeutic effect in 15 of 20 women with DO[Gruneberger, 1984]. Other investigators, however,have not been able to show that β-ARs agonistsrepresent an effective therapeutic principle in elderlypatients with DO [Castleden and Morgan, 1980], orin young patients with myelodysplasia and DO [Nagloet al, 1981].

However, three subtypes (β1, β2, and β3) have beenidentified in the detrusor of most species, includinghumans [Andersson and Arner, 2004; Michel andVrydag, 2006]. Also the human urothelium containsall three receptor subtypes [Otsuka et al., 2008].Studies, using real-time RT-PCR, have revealed apredominant expression of β3-AR mRNA in humandetrusor muscle [Nomiya and Yamaguchi, 2003; Micheland Vrydag, 2006] and the functional evidence for animportant role in both normal and neurogenic bladdersis convincing [Fujumura et al., 1999; Igawa et al.,1999; Takeda et al., 1999; Morita et al., 2000; Igawaet al., 2001; Biers et al., 2006; Michel and Vrydag,2006; Badawi et al., 2007; Leon et al., 2008]. Thehuman detrusor also contains β2-ARs, and mostprobably both receptors are involved in thephysiological effects (relaxation) of noradrenaline inthis structure [Andersson and Arner 2004; Michel andVrydag, 2006].

The generally accepted mechanism by which β-ARsinduce detrusor relaxation in most species, is activationof adenylyl cyclase with the subsequent formation ofcAMP. However, there is evidence suggesting that inthe bladder K+ channels, particularly BKCa channels,may be more important in β-AR mediated relaxationthan cAMP [Hudman et al., 2000; Frazier et al., 2005;Uchida et al., 2005; Frazier et al., 2008].

Since β-ARs are present in the urothelium, theirpossible role in bladder relaxation has beeninvestigated [Murakami et al., 2007; Otsuka et al.,2008]. Murakami et al. [2007] found that the relaxationresponses of the detrusor were not influenced by theurothelium. However, isoprenaline was more potentat inhibiting carbachol contractions in the presence ofthe urothelium than in its absence. It was suggestedthat this might reflect the release of an inhibitory factorfrom the urothelium. Further support for this hypothesiswas given by Otsuka et al. [2008]. However, to whatextent a urothelial signaling pathway contributes in vitroand in vivo to the relaxant effects of β-AR agonists ingeneral, and β3-AR agonists specifically, remains to

be elucidated.

The in vivo effects of β3-AR agonists on bladderfunction have been studied in several animal models.It has been shown that compared with other agents(including antimuscarinics), β3-AR agonists increasebladder capacity with no change in micturition pressure

and the residual volume [Fujimura et al., 1999; Woodset al., 2001; Takeda et al., 2002; Kaidoh et al., 2002].For example, Hicks et al. [2007] studied the effects ofthe selective β3-AR agonist, GW427353, in theanesthetized dog and found that the drug evoked anincrease in bladder capacity under conditions of acidevoked bladder hyperactivity, without affecting voiding.

A number of β3-AR selective agonists are currentlybeing evaluated as potential treatment for OAB inhumans including GW427353 (solabegron) andYM178 [Colli et al., 2007]. Takaku et al. [2007] foundthat the selective β3 -AR agonist, YM187, mediatedmuscle relaxation of human bladder strips. Chappleet al. [2008] reported the results of a controlled clinicaltrial with this drug in patients with OAB. Tolterodineand placebo served as controls. The primary efficacyanalysis showed a statistically significant reductionin mean micturition frequency, compared to placebo(-2.19 vs -1.18). With respect to secondary variablesYM178 (100 mg) was significantly superior to placeboconcerning mean volume voided per micturition (26vs 11 ml), mean number of incontinence episodes (-2.17 vs -1.01), and urgency episodes per 24 hour(-2.30 vs -1.03). The drug was well tolerated, and themost commonly reported side effects were headacheand gastrointestinal adverse effects. The results ofthis proof of concept study showed that the principleof β3-AR agonism may be useful for treatment ofpatients with OAB (Table 2). However, to show thatthis class of drugs offers a viable therapeutic alternativeor complement to current treatment of LUTS/OABrequires further well designed RCTs.

Drugs stimulating the generation of cAMP are knownto relax smooth muscles, including the detrusor[Andersson 1999; Andersson and Arner, 2004]. It isalso well established that drugs acting through theNO/cGMP system can relax the smooth muscle ofthe bladder outflow region [Andersson and Arner,2004]. Use of PDE inhibitors to enhance the presumedcAMP- and cGMP-mediated relaxation of LUT smoothmuscles (detrusor prostate, urethra) should then bea logical approach [Andersson et al., 2007]. Thereare presently 11 families of PDEs, some of whichpreferentially hydrolyse either cAMP or cGMP[Andersson et al. 2007].

As a basis for PDE inhibitor treatment of LUTS, Uckertet al. [2001] investigated human bladder tissue,revealing messenger RNA for PDEs 1A, 1B, 2A, 4A,4B, 5A, 7A, 8A, and 9A; most of these PDEs preferablyinhibit the breakdown of cAMP. In vitro, human detrusormuscle responded poorly to sodium nitroprusside,and to agents acting via the cGMP system [Truss etal., 2001]. However, significant relaxation of human

VI. PHOSPHODIESTERASE (PDE)INHIBITORS

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detrusor muscle, paralleled by increases in cyclicnucleotide levels, was induced by papaverine,vinpocetine (a low affinity inhibitor of PDE 1), andforskolin (stimulating the generation of cAMP),suggesting that the cAMP pathway and PDE 1 maybe important in regulation of detrusor smooth muscletone. Significant dose-dependent relaxations werealso induced by human cAMP analogs [Truss et al.,2001]. With these studies as a background, Truss etal. [2000] presented preliminary clinical data withvinpocetine in patients with urgency/urgencyincontinence or low compliance bladders, and notresponding to standard antimuscarinic therapy. Thisinitial open pilot study suggested a possible role forvinpocetine in the treatment of OAB. However, theresults of a larger RCT in patients with DO showedthat vinpocetine showed statistically significant resultsonly for one parameter [Truss et al., 2001]. Studieswith other PDE 1 inhibitors than vinpocetin (whichmay not be an optimal drug for elucidation the principle)do not seem to have been performed.

PDE 4 (which also preferably hydrolyses cAMP) hasbeen implicated in the control of bladder smoothmuscle tone. PDE 4 inhibitors reduced the in vitrocontractile response of guinea pig [Longhurst et al.,1997] and rat [Nishiguchi et al., 2006; Kaiho et al.,2008] bladder strips, and also suppressed rhythmicbladder contractions of the isolated guinea pig bladder[Gillespie, 2004]. Previous experiences with selectivePDE 4 inhibitors showed emesis to be a dose -limitingeffect [Giembycz, 2005]. If this side action can beavoided, PDE 4 inhibition seems to be a promisingapproach.

Nitric oxide (NO) has been demonstrated to be animportant inhibitory neurotransmitter in the smoothmuscle of the urethra and its relaxant effect isassociated with increased levels of cyclic GMP[Andersson and Wein, 2004]. However, fewinvestigations have addressed the cAMP- and cGMP-mediated signal transduction pathways and its keyenzymes in the mammalian urethra. Morita et al.[1994] examined the effects of isoproterenol,prostaglandin E1 and E2, and SNP on the contractileforce and tissue content of cAMP and cGMP in therabbit urethra. They concluded that both cyclicnucleotides can produce relaxation of the urethra.Werkström et al. [2006] characterized the distributionof PDE 5, cGMP and PKG1 in female pig and humanurethra, and evaluated the effect of pharmacologicalinhibition of PDE-5 in isolated smooth musclepreparations. After stimulation with the NO donor,DETA NONO-ate, the cGMP-immunoreactivity (IR)in urethral and vascular smooth muscles increased.There was a wide distribution of cGMP- and vimentin-positive interstitial cells between pig urethral smoothmuscle bundles. PDE-5 IR could be demonstratedwithin the urethral and vascular smooth muscle cells,but also in vascular endothelial cells that expressedcGMP-IR. Nerve-induced relaxations of urethral

preparations were enhanced at low concentrationsof sildenafil, vardenafil and tadalafil, whereas therewere direct smooth muscle relaxant actions of thePDE-5 inhibitors at high concentrations.

The distribution of PDEs in the male urethral structuresdoes not seem to have been studied.

The observation that patients treated for erectiledysfunction with PDE 5 inhibitors had an improvementof their LUTS, has sparked a new interest in usingthese drugs also for treatment of LUTS and OAB.After the report in an open study [Sairam et al., 2002]that treatment with sildenafil appeared to improveurinary symptom scores in men with ED and LUTS,this observation has been confirmed in several welldesigned and conducted RCTs [McVary et al., 2007a;b,Stief et al., 2008].

McVary et al. [2007a] evaluated the effects of sildenafil(50-100 mg daily for 12 weeks) on erectile dysfunctionand LUTS in men men 45 years or older who scored25 or less on the erectile function domain of theInternational Index of Erectile Function (IIEF) and 12or greater on the International Prostate SymptomScore (IPSS). In 189 men receiving sildenafilsignificant improvements were observed in IPPS (-6.32vs -1.93, p<0.0001), Benign Prostatic HyperplasiaImpact Index (-2.0 vs -0.9, p<0.0001), mean IPSSquality of life score (-0.97 vs -0.29, p<0.0001) andtotal Self-Esteem and Relationship questionnairescores (24.6 vs 4.3, p<0.0001). Interestingly, therewas no difference in urinary flow between the groups(p=0.08). Significantly more sildenafil vs placebotreated patients were satisfied with treatment (71.2 vs41.7, p<0.0001). Sildenafil was well tolerated.

In an RCT, treatment with tadalafil once daily, inaddition to improving erectile function in men withLUTS, was demonstrated to produce a clinicallymeaningful and statistically significant symptomaticimprovement of LUTS [McVary et al., 2007b]. Inanother RCT, vardenafil given twice daily for eightweeks to men with ED and LUTS, was shown tosignificantly improve LUTS, erectile function, andquality of life Stief et al. [2008].

The mechanism behind the beneficial effect of thePDE inhibitors on LUTS/OAB and their site(s) of actionlargely remain to be elucidated. If the site of action werethe smooth muscles of the outflow region (and theeffect relaxation), an increase in flow rate should beexpected. In none of the trials referred to such aneffect was found. However, there are several otherstructures in the LUT that may be involved, includingthose in the urothelial signaling pathway (urothelium,interstital cells, and suburothelial afferent nerves).

PDE-5 inhibitors have a documented effect in men withLUTS/OAB (Table 2). The place of PDE-5 inhibitorsin the treatment of OAB/DO remains to be established.Specifically, there seems to be no publishedinformation the effects of these drugs in women withOAB/DO.

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1. IMIPRAMINE

Several antidepressants have been reported to havebeneficial effects in patients with DO [Martin andSchiff, 1984, Lose et al., 1989]. However, imipramineis the only drug that has been widely used clinicallyto treat this disorder.

Imipramine has complex pharmacological effects,including marked systemic antimuscarinic actions[Baldessarini, 1985] and blockade of the reuptake ofserotonin and noradrenaline [Maggi et al., 1989], butits mode of action in DO has not been established[Hunsballe and Djurhuus, 2001]. Even if it is generallyconsidered that imipramine is a useful drug in thetreatment of DO, no good quality RCTs that candocument this have been retrieved.

It has been known for a long time that imipraminecan have favourable effects in the treatment ofnocturnal enuresis in children with a success rate of10-70 % in controlled trials [Hunsballe and Djurhuus,2001; Glazener et al., 2003]. It is well established thattherapeutic doses of tricyclic antidepressants, includingimipramine, may cause serious toxic effects on thecardiovascular system (orthostatic hypotension,ventricular arrhythmias). Imipramine prolongs QTcintervals and has an antiarrhythmic (and proarrhythmic)effect similar to that of quinidine [Bigger et al, 1977;Giradina et al., 1979]. Children seem particularlysensitive to the cardiotoxic action of tricyclicantidepressants [Baldessarini, 1985].

The risks and benefits of imipramine in the treatmentof voiding disorders do not seem to have beenassessed. Very few studies have have been performedduring the last decade [Hunsballe and Djurhuus,2001]. No good quality RCTs have documented thatthe drug is effective in the treatment DO (Table 2).However, a beneficial effect has been documented inthe treatment of nocturnal enuresis.

2. DULOXETINE

Duloxetine is a combined noradrenaline and serotoninreuptake inhibitor, which has been shown tosignificantly increase sphincteric muscle activity duringthe filling/storage phase of micturition in the cat aceticacid model of irritated bladder function [Thor et al.,1995; Katofiasc et al, 2002]. Bladder capacity wasalso increased in this model, both effects mediatedcentrally through both motor efferent and sensoryafferent modulation [Fraser et al., 2003]. The effectsof duloxetine were studied in a placebo-controlledstudy comprising 306 women (aged 21-84 years) withOAB, randomly treated with placebo (153) orduloxetine (80-mg/day for 4 weeks, which wasincreased to 120-mg/day for eight weeks [Steers etal., 2008]. The primary efficacy analysis compared

the treatment effects on mean change from baselineto endpoint in the mean number of voiding episodesper 24 hours. Patients randomized to duloxetine hadsignificant improvements over those randomized toplacebo for decreases in voiding and incontinenceepisodes (-1.81 vs -0.62), for increases in the daytimevoiding intervals (29 vs 7 minutes), and forimprovements in I-QoL scores at both doses of thedrug. Urodynamic studies showed no significantincreases in maximum cystometric capacity or in thevolume threshold for DO. The most commontreatment-emergent adverse events with duloxetine(nausea, 31%, placebo, 4.6; dry mouth, 16%, placebo,1.3; dizziness, 14%, placebo 0.7; constipation, 14%,placebo, 3.3; insomnia, 13%, placebo1.3; and fatigue,11%, placebo 2.0) were the same as those reportedby women with SUI (see below) and were significantlymore common with duloxetine than placebo. Also infemales with mixed incontinence, improvement of theOAB component has been demonstrated [Bent et al.,2008; Schagen van Leeuwen et al., 2008]. Forassessment, see Table 2.

Human bladder mucosa has the ability to synthesizeeicosanoids [Jeremy et al., 1987], and these agentscan be liberated from bladder muscle and mucosa inresponse to different types of trauma [Downie andKarmazyn, 1984; Leslie et al., 1984]. Even ifprostaglandins cause contraction of human detrusor[Andersson, 1993], it is still unclear whetherprostaglandins contribute to the pathogenesis of DO.More important than direct effects on the bladdermuscle may be sensitization of sensory afferentnerves, increasing the afferent input produced by agiven degree of bladder filling. Involuntary bladdercontractions can then be triggered at a small bladdervolume. If this is an important mechanism, treatmentwith prostaglandin synthesis inhibitors could beexpected to be effective. However, clinical evidencefor this is scarce.

Cardozo et al. [1980] performed a double-blindcontrolled study of 30 women with DO using theprostaglandin synthesis inhibitor flurbiprofen at adosage of 50 mg three times daily. The drug wasshown to have favourable effects, although it did notcompletely abolish DO. There was a high incidenceof side effects (43%) including nausea, vomiting,headache and gastrointestinal symptoms. Palmer[1983] studied the effects of flurbiprofen 50 mg x 4versus placebo in a double-blind, cross-over trial in37 patients with idiopathic DO (27% of the patients didnot complete the trial). Active treatment significantlyincreased maximum contractile pressure, decreasedthe number of voids and decreased the number ofurgent voids compared to baseline. Indomethacin 50to 100 mg daily was reported to give symptomaticrelief in patients with DO, compared with bromocriptinein a randomized, single-blind, cross-over study

VII. ANTIDEPRESSANTS

VIII. CYCLOOXYGENASE (COX) INHIBITORS

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[Cardozo and Stanton, 1980]. The incidence of sideeffects was high, occurring in 19 of 32 patients.However, no patient had to stop treatment becauseof side effects.

The few controlled clinical trials on the effects ofprostaglandin synthesis inhibitors in the treatment ofDO, and the limited number of drugs tested, makesit difficult to evaluate their therapeutic value (Table2).

No new RCTs on the effects of COX inhibitors inOAB/DO patients seem to have been published duringthe last decade.

The persisting interest around intravesicalpharmacological therapy for neurogenic DO (NDO)stems from the fact that it circumvents systemicadministration of active compounds. This offers twopotential advantages. First, intravesical therapy is aneasy way to provide high concentrations ofpharmacological agents in the bladder tissue withoutcausing unsuitable levels in other organs. Second,drugs effective on the bladder, but inappropriate forsystemic administration, can be safely used. This isthe case of botulinum toxin (BONT) and vanilloids.Attractive as it may be, intravesical pharmacologicaltherapy should still be considered as a second linetreatment in patients refractory to conventional oralantimuscarinic therapy or who do not tolerate itssystemic side effects. For assessments, see Table 2.

1. BOTULINUM TOXIN

a) Mechanism of action of BONT

Botulinum toxin (BONT) is a neurotoxin produced byClostridium botulinum. Of the seven subtypes of BONT,sub-type A (BONT-A) is the most relevant clinically.Most of the intravesical experience reported on BONT-A deals with Botox®. However, BONT-A toxin is alsoavailable under the trade names of Dyspor®‚ andXeomin‚. Bladder experience with the latter was,however, never reported. Available informationindicates that Botox® is roughly three times morepotent than Dyspor® [Cruz and Silva, 2004; Nitti et al,2006]. However this relation has never been clearlydefined. Therefore at a bladder setting theseequivalents should be approached with caution [forclinical reviews, see Nitti et al., 2006; Patel et al.,2006; Cruz and Dinis, 2007; Karsenty et al, 2008]. Inaddition to sub-type A, recent reports have investigatedthe detrusor injection of BONT sub-type B(Neurobloc®, Miobloc®). For further details see section9.1.9.

BONT consists of a heavy and a light chain linked bya disulphide bond. In the synaptic cleft the toxin bindsto synaptic vesicle protein or SV2 [Dong et al., 2006]

through its heavy chain and is internalized by thenerve terminal. Upon cleavage, the light chain isreleased in the cytosol, where it impedes binding ofneurotransmitter-containing synaptic vesicles to theplasma membrane. This is achieved through the N-ethylmaleimide-sensitive factor attachment protein(SNARE) complex made up of synaptosomeassociated protein 25 kD (SNAP 25), synaptobrevin(vesicle associated membrane protein -VAMP) andsyntaxin. BONT-A cleaves SNAP 25 rendering theSNARE complex inactive [Humeau et al., 2000;Chancellor et al., 2008]. Subtype B, acts preferentiallythrough the inactivation of VAMP [Humeau et al.,2000].

BONT-A application was extensively evaluated instriated muscle. Paralysis occurs by prevention ofACh release from cholinergic motor nerve endings[Humeau et al, 2000]. Accumulation of neurotransmittercontaining synaptic vesicles is followed by terminalaxonal degeneration. Muscular paralysis recoverswithin two to four months time. During this time axonsare developing lateral sprouts and eventuallyregenerate completely [de Paiva et al., 1999]. Asparasympathetic cholinergic nerves are alsofundamental for detrusor contraction the blockade ofACh release was immediately put forward as therationale for the neurotoxin effect when injected inthe bladder. However axon sprouting concomitantwith clinical remission has not been documented inthe detrusor [Haferkamp et al., 2004]. Furthermorefragments of cleaved SNAP 25 are detectable inbladder biopsy specimens of patients treatedintravesically with BONT-A long after they becomeundetectable in striated muscle [Schulte-Baukloh etal., 2007]. These facts indicate that additionalmechanisms of action are probably operative in thebladder. BONT-A inhibits the spinal cord release ofglutamate, Substance P (SP) and CGRP by sensorynerves [Aoki et al., 2005; Purkiss et al., 2000; Menget al., 2007] as well as the release of neuropeptidesat the peripheral extremities [Lucioni et al., 2008;Rapp et al., 2006]. In the bladder, BONT-A has beenshown to reduce the suburothelial immunoreactivityfor TRPV1 or P2X3 [Apostolidis et al, 2005].Furthermore BONT-A has been shown to inhibit ATPrelease from urothelium in animal models of spinal cordinjury [Khera et al, 2004; Smith et al., 2008]. MorenillaPalao et al. [2004] have shown co-localization ofSNARE proteins and TRPV1 in sensory nerves andthat BONT-A impedes TRPV1 trafficking fromintracellular vesicles to the plasma membrane duringinflammation.

BONT-A may decrease the levels of neurotrophicagents in the bladder tissue. Neurogenic DO (NDO)patients produce more Nerve Growth Factor (NGF)in the bladder than control individuals [Giannantoni etal, 2006; Liu et al, 2008] and a significant decreasecan be detected after intravesical the application of

IX. TOXINS

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the toxin. As NGF is paramount for sensory nervegrowth, maintenance and plasticity, this finding maypoint toward another mechanism whereby BONT-Aacts upon the bladder.

b) BONT-A injection protocol

When the treatment was first described in 1999,BONT-A (Botox®) was diluted in normal saline inorder to obtain a concentration of 10 Units/ml [Schurchet al., 2000]. Under visual control through a rigidcystoscope and a flexible 6 Fr injection needle, 30injections of 1 ml (10 Units (U) of BONT-A toxin) weredone in 30 different locations above the trigone toprevent vesico-urethral reflux (Figure 13). Additionalrefinements have been added to this technique alongthe following years, including the use of a localanaesthetic agent (4% lidocaine) and a flexiblecystoscope [Harper et al., 2003]. For Dyspor® thetechnique was similar, including the number of injectionsites. Only the dilutions were different taking inconsideration that 500-1000 U were used [Cruz andSilva, 2004].

The effect of BONT-A after increasing the dose perinjection site and decreasing the number of injectedsites was investigated in one study. Patients wererandomized to receive 300 U either in 10 or 30 sites[Karsenty et al., 2005]. The authors reported that 10-site injection was quicker and less painful and that nodifferences in efficacy between the two procedurescould be detected up to 24 weeks. Another variationis the neurotoxin injection in the trigone. The suggestedrisks of injecting bladder trigone has never beendemonstrated, whether Botox® or Dyspor® was used[Karsenty et al., 2007; Mascarenhas et al., 2008; Citeriet al., 2008]. However, this does not mean that trigonalinjections bring marked benefits to the treatment. Onetrial concluded that 100 U of Botox® injected only in

the trigone were less effective and durable than whenadministered in the detrusor [Kuo et al., 2007]. Injectionin the sub-urothelial space was also assayed on thesuggestion that in this position the BONT-A effectcould be more pronounced in sensory than inparasympathetic motor fibers (Kuo et al., 2005).However, in one comparative study injection of 100U of Botox® in the suburothelial space was lesseffective than in the detrusor [Kuo et al., 2007]. Anothervariable of the injection technique is the diluent volume.Most studies used 1.0 mL per injection, although a fewused 0.5 mL [Grosse et al., 2005; Schulte-Baukloh etal., 2005), 0.2 mL (Kuo et al., 2004), or even 0.1 mLper injection site [Rapp et al., 2004]. In conclusion, atthis point it must be concluded that further controlledstudies designed to compare different number andlocals of injections sites are necessary.

c) Effect of BONT-A on NDO adult patients

Following the preliminary report of BONT-A (Botox®,200 or 300U) detrusor application in 21 patients withtraumatic spinal cord injury resistant to antimuscarinicdrugs [Schurch et al., 2000a; b], a large multicenternon-controlled clinical trial was conducted in Europeenrolling 231 NDO patients, most with spinal cordinjury [Reitz et al., 2004]. Botox®, 300 U was injectedin 30 points in the detrusor above the trigone. Datawere available for 200 patients. In 180 incontinentpatients, this study, which still represents the largesttrial conducted with BONT-A, brought urinarycontinence to 132 and a marked improvement to 48patients. A marked increment of the volume for firstdetrusor contraction and decline of maximal detrusorpressure were observed during urodynamicevaluations up to 36 weeks after injection. No injectionrelated complications or toxin side effects werereported. Several other non-controlled studies

Figure 13 : Techniques for injectionof BoNT-A in the bladder.

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published subsequently confirmed these observations[see, Patel et al., 2006; Dmochowski et al., 2007;Karsenty et al., 2008 for review].

Botox® and Dyspor® efficacy in NDO was alsodemonstrated in small double blind placebo controlledtrials [Schurch et al., 2005; Ehren et al, 2007]. Fifty-nine NDO patients due to spinal cord injury wererandomized to receive Botox®, 200 U, 300 U orplacebo. BONT-A treated patients showed a significantreduction in incontinence episodes and ameliorationof urodynamic parameters versus placebo that weremaintained in the 6 month observation period.Unfortunately the study was not powered to detectdifferences between 200 and 300 U of BONT-A[Schurch et al., 2005]. In a further subanalysis, asingle dose of BONT-A 300 U significantly improvedtotal and subscale I-QoL scores compared withplacebo at all time points [Schurch et al., 2007].

Another small single center study randomized a totalof 31 NDO patients due to spinal cord injury,myelomeningocele, trauma at birth, multiple sclerosisand myelitis to intravesical injections of either 500 Uof Dyspor® or placebo [Ehren et al, 2007]. Intake oftolterodine and episodes of urinary leakage wereregistered. Cystometry was performed after 6, 12 and26 weeks and quality of life was assessed. Patientsin the BONT-A arm had a significantly highercystometric capacity at 6 and 12 weeks. Maximumdetrusor pressure and episodes of urinary leakageand tolterodine consumption were significantly lowerin the BONT-A than in the placebo group.

In general, the reported duration of BONT-A effect inNDO patients (Botox®, 300U) ranged between 6 and9 months at the first injection [see, Cruz and Silva,2004; Dmochowski et al., 2007; Karsenty et a., 2008for reviews]. The duration of subsequent injectionswas investigated by three studies along severalconsecutive injections. Del Popolo et al. [2008] studiedthe long term effect of BONT-A (Dyspor®) in 199spinal cord injured patients over a period of 6 years.Initial doses ranged from 500 to 1000 but subsequentlythe 1000 U dose was abandoned to avoid side effects(see below). The duration of the effect averaged 12months and was similar for all the three doses.Urodynamic and clinical improvements detected atthe first injection were maintained at each re-injection,associated with a highly significant improvement inpatient´s satisfaction. Reitz and co-workers [2007]studied intradetrusor BONT-A (Botox®) injections in20 patients who received at least five intradetrusorinjections for long term treatment of NDO. Continence,volume to first detrusor contraction, maximumcystometric capacity, maximum detrusor pressureand compliance at baseline improved significantlyafter the first injection and at all re-injections. Injectionintervals, in average 7 months, tended to lengthenwith repeat injections albeit insignificantly. Anotherstudy used Botox® 300 U or Dyspor® 750 U in 44 and

22 spinal NDO patients, respectively. Although mostof the patients had 2-4 injections, a few had up to 7consecutive injections. The interval betweensubsequent injections averaged 9–11 months at allinjections. The antimuscarinic use decreasedsubstantially. Significant improvements were foundin clinical parameters and in cystometric capacity,whereas compliance improved only after the secondtreatment. The incidence of DO was significantlyreduced. Four patients had transient adverse eventsafter Dyspor® [Grosse et al., 2005].

The onset of BONT-A effect starts within the first 2weeks after neurotoxin injection [Cruz and Silva, 2004;Dmochowski et al., 2007; Karsenty et al., 2008]. Thistime course was further evaluated in a small open-labelprospective study that specifically investigated thechronology of the BONT-A effects. Urgency, nocturiaand frequency were shown to improve as soon astwo days after neurotoxin injection in NDO patients[Kalsi et al., 2008].

The majority of the patients included in the BONT-Atrials, whether open label or controlled, were spinalcord injured patients [Cruz Silva., 2004; Dmochowskiet al., 2007; Karsenty et al., 2008]. The few patientswith multiple sclerosis that were included were neveranalyzed separatedly. Such a gap was filled recentlywith the study of BONT-A in a MS cohort. Forty-threeMS patients suffering from severe urgency andincontinence were treated with 300 U BONT-A(Botox®) [Kalsi et al., 2007]. Highly significantimprovements in urgency, incontinence episodes,frequency and nocturia were observed. In addition,bladder capacity, volume to detrusor overactivity andmaximal detrusor pressure also improved. The meanduration of the effect was 9.7 months. Similar resultswere seen with repeat treatments. However, all but oneof the treated patients had to perform self-catheterization after treatment. In spite of thisdrawback, authors concluded that the treatment waslikely to have a major impact on future managementof multiple sclerosis patients with detrusor overactivity[Kalsi et al., 2007].

d) BONT-A and urinary tract infection (UTI) inadult NDO patients

A consequence of BONT-A treatment only recentlynoticed is a decrease in the incidence of urinary tractinfections in NDO patients. In 30 SCI patients, Gaméet al. [2008] observed that the number ofpyelonephritis, orchitis and prostatitis in the six monthsbefore BONT-A, 1.75±1.87 per patient, decreased to0.2±0.41 in the first six months after treatment. In 17SCI patients that received BONT-A (Botox®) injectionsfor a period of six years, the number of urinary tractinfection at the sixth year was 1.8±0.5 per year,significantly lower than at baseline, 6.7±2.1[Giannantoni et al., 2008]. In a multicentre, cross-sectional retrospective cohort study, data from 214

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NDO patients treated in seven German centers werecollected. The rate of urinary tract infections in 12months preceding and in the 12 months followingBONT-A (Botox®) treatment was 68% and 28%,respectively [Boy et al., 2008]. The reason for thesefindings is unclear but may lie in a decreased maximumdetrusor pressure resulting in less bladder wallischemia and vesico-ureteral reflux.

e) BONT-A in NDO children

In children, the dose of BONT-A (Botox®) should becalculated according to body weight. Doses of between12 U/kg of weight up to a maximum dose of 300 U[Schulte-Baukloh et al., 2002] and four U/Kg [Corcoset al., 2002] have been used for Botox®. The maximumsuggested Dysport® dose was 20 U/kg up to amaximum of 400 U [Altaweel et al., 2006, Akbar et al.,2007]. BONT-A has been essentially assayed inchildren with myelomeningocele [Schulte-Baukloh etal., 2002; Schulte-Baukloh et al., 2003; Corcos et al.,2002; Riccabona et al., 2004; Kajbafzadeh et al.,2006; Altaweel et al., 2006]. Like in adults, the toxinincreased bladder capacity and decreased maximaldetrusor pressure. In 26 children with a mean age of6.9 years, 19 of them (73%) became completely drybetween clean intermittent catheterizations while 88%reported a global improvement in urine incontinence.Interestingly, of the 15 children who had vesicoureteralreflux before the procedure, 11 (73%) foundimprovement, which either disappeared or decreasedin grade. BONT-A also improved bowel function in66% of the children with intestinal problems[Kajbafzadeh et al., 2006].

The success rate in terms of continence and cessationof antimuscarinic medication may, however, besubstantially inferior to that seen in adults, potentiallydue to irreversible bladder wall changes associatedwith longstanding detrusor overactivity [Altaweel etal., 2006]. In a group of 20 children with myelo-meningocele continence was achieved in only 13children. At a second injection, this number also didnot change appreciably [Altaweel et al., 2006].

f) BONT-A in idiopathic DO (IDO) patients

When compared to NDO, information existing on theuse of BONT-A in IDO patients refractory toantimuscarinic agents is more scarce and based onsmall clinical trials. However, the results of BONT-Aapplication in the bladder of NDO patients and thesuccess of recent trials are pushing more and moreclinicians to offer the neurotoxin to their patients beforeits approval for bladder administration.

In the first report, by Radziszewski and Borkowski[2002], 300 UI of Dyspor® were injected in 10-20bladder sites of 12 IDO patients. Bladder capacityincreased significantly, all patients became continentand no side effects were reported, including urinaryretention. However subsequent studies reported in

general a high incidence of voiding dysfunction. Kuo[2004] reported on 18 IDO patients detrusor injectionsof BONT-A (Botox®, 200 U). Continence was regainedin seven patients (39%) and another seven (39%)reported some degree of clinical improvement. Meanduration of effect was 5.3 months. However, six (33%)patients required clean intermittent catheterization(CIC) at one month to empty their bladders [Kuo etal., 2004]. Popat et al. (2005) also injected 200 U ofBotox® in the detrusor and reported at 16 weeks aclear improvement in urgency, urgency incontinencefrequency and maximal cystometric capacity. Six

patients (19.3%) required prolonged CIC. Sub-urothelial injections were suggested to decrease theincidence of urinary retention, by preferentiallytargetting suburothelial sensory fibers. However, in20 patients who received suburothelial BONT-A(Botox®, 200 U) urinary retention occurred in six(30%) [Kuo et al., 2005].

The results of these open label studies were confirmedin two albeit small double-blind, placebo controlledtrials in which patients were randomized tointradetrusor injections of 200 U BONT-A (Botox®)or placebo [Sahai et al., 2007; Brubaker et al., 2008].Sahai et al. [2007] used maximum cystometric capacityas primary outcome measure and changes inoveractive bladder symptoms, post-void residual,maximum detrusor pressure during filling cystometry,reflex detrusor volume and QoL questionnaires assecondary outcome measures. Follow-up occurredat four and 12 weeks after injection, at which point thestudy was unblinded. Further followup in the BONT-A group occurred at 24 weeks. Significant increasesin maximum cystometric capacity were observed atfour and 12 weeks in patients treated with BONT-Acompared to placebo. BONT-A also reduced frequencyand urgency incontinence episodes at four and 12weeks. Urgency was significantly reduced only at fourweeks in BONT-A group. Post-void residual increasedat four weeks in patients receiving BONT-A, butdifferences to placebo became insignificant by 12weeks. Despite significant improvements in qualityof life observed among patients treated with BONT-A, 37.5% of them required intermittent self-cathe-terization to empty the bladder. Brubaker et al. [2008]randomized 28 women to Botox® 200 U and 15 forplacebo. Approximately 60% of the women whoreceived BONT-A had a clinical response based onthe Patient Global Impression of Improvement. Themedian duration of their responses was 373 days,significantly longer than the 62 days or less for placebo.Post-void residual urine increased in 43% of thewomen in the BONT-A group (12 out of 26 women)and urinary tract infection developed in 75% of thesewomen (9 of 12). These numbers exceeded by farthe expected ranges and forced the suspension ofscreening and injection. Median duration of urinaryretention after the first injection was approximately

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two months but increased to five months at a secondinjection [Brubaker et al., 2008].

The obvious necessity of reducing micturitiondysfunction after BONT-A injections is beinginvestigated through a substantial reduction in theamount of neurotoxin delivered into the detrusor.Schmid et al. [2006] injected 100 U of Botox® in 100IDO patients refractory to antimuscarinic therapy.BONT-A treatment completely abolished incontinenceand urgency sensation in 86% and 82% of patients,respectively, during an average period of six months.Temporary urinary retention occurred in four % of thecases, with additional 15% reporting moderate voidingdifficulties. In a recent update of this experience[Schmid et al., 2008] an increase in the duration ofBONT-A effect upon repeated injections was observed.Kuo and co-workers [2007] randomly compareddetrusor, suburothelial and bladder base injectionsof 100 U BONT-A (Botox®) in 45 IDO patientsrefractory to antimuscarinic therapy. Urgency scoresimproved significantly in all groups. However, durationof clinical improvement was different in the threegroups. Percentage of patients with clinicalimprovement after detrusor, suburothelial and bladderbase injections was 67%, 47% and 13% by six monthsand to 20%, 20% and 6.7% at nine months,respectively. At three months significant increases incystometric capacity and post-void residual comparedto baseline were found in the detrusor and suburothelialbut not in the bladder base group. Vesicoureteralreflux was not identified in any patient after BONT-Ainjection into the trigone.

The definition of an ideal dose of BONT-A for IDOpatients as well as the ideal local of injections willrequire further well designed clinical trials. In additionit is unclear at this time what percentage of IDOpatients can stop antimuscarinic medication. Forassessment, see Table 2).

A small open-label prospective study specificallyinvestigated the chronology of the BONT-A effects inIDO patients. Urgency, nocturia and frequencyimproved as soon as four days in IDO patients,therefore slightly later than in NDO cases [Kalsi etal., 2008].

g) Effect of BONT-A on quality of life

Quality of life (QoL) in NDO patients treated withintravesical BONT-A has been addressed in severalstudies. Kalsi et al. [2006] examined QOL changes in32 NDO and 16 IDO patients, using the short formsof the Urinary Distress Inventory (UDI-6) andIncontinence Impact Questionnaire (IIQ-7). Highlysignificant decreases in QoL scores at four and 16weeks for both the NDO and IDO subgroups wereobserved. Percent improvement in QoL score wassimilar for both groups of patients. A multicenter,randomized, double blind placebo controlled trialconfirmed these data [Schurch et al., 2007]. Fifty-

nine NDO patients with urinary incontinence receiveda single dose of BONT-A (200U or 300 U, Botox®) orplacebo. I-QoL scores improved significantly withBONT-A, whether 300U or 200 U were used. A singlecenter, double blind, placebo controlled study wasperformed by Ehren et al. [2007] to evaluate the effectof a single injection of 500 U of BONT-A (Dysport ®)on quality of life in 31 NDO patients with incontinence.Patients were randomized to intravesical injectionsof either 500 U of BONT-A or placebo. Patients in theBONT-A group showed improved quality-of-lifeparameters compared to the placebo group [Ehren etal., 2007]. Unlike the previous studies, in which patientshad various neurological conditions, a recent studymeasured the efficacy and impact on quality of life ofBONT-A (300 U of Botox® ®) in 43 patients withmultiple sclerosis [Kalsi et al., 2007]. There was a45% decrease in urinary frequency, 77% decrease inincontinence episodes, 78 % decrease in micturitionepisodes associated with urgency and a 47 %decrease in nocturia. Although 98% of patients hadto perform self-catheterization after treatment, therewere sustained improvements in all quality-of-lifescores with a mean duration of effect of 9.7 months.Results were maintained with repeat treatments (twoinjections in 18 and three in two patients) for 11.7months.

h) Side effects of intradetrusor BONT-A

One of the most frequent side effects reported afterintradetrusor BONT-A injection is bladder pain[Karsenty et al., 2008; Del Popolo et al., 2008].Hematuria may also occur, most of the times mild innature. The most feared one, paralysis of the striatedmusculature due to circulatory leakage of the toxin hasnever been reported. Transient muscle weaknesswas however reported with Dysport® application inseveral studies [Wyndaele and Van Dromme, 2002;Akbar et al., 2007; Del Popolo et al., 2008]. Among199 NDO patients followed during 8 years, fivedeveloped hypostenia when injected with 1000 U ofDyspor®. In another study with 44 patients, threeadults also treated with 1000 units developed muscularweakness which subsided after 5 to 7 weeks [Akbaret al., 2007]. No such cases were reported with Botox®BONT-A [Karsenty et al., 2008]. The reason for the lackof transient muscle weakness among Botox®-treatedpatients is unclear but might be related with the largersize of its molecule which limits diffusion into the bloodstream. The risk of hyposthenia associated withDysport® might be avoided by using lower doses ofthe toxin, no more that 750 units for adults and 20 U/kgfor children [Akbar et al., 2007; Del Popolo et al.,2008]. In addition, caution should be used in selectinghigh risk patients for botulism including children,patients with low pulmonary reserve or patients withmyasthenia gravis. Aminoglycosides should beavoided during BONT-A treatment since they mightblockade motor plates and therefore enhance BONT-A effect.

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Fear of vesicoureteral reflux, which for long precludedtrigone injections [Schurch et al., 2000a; Reitz et al.,2004] seems unfounded whether Botox® or Dysport®is used [Karsenty et a., 2007; Mascarenhas et a.,2008; Citeri et a., 2008; Eichel et al., 2008]. Howevertrigonal injections may not enhance BONT-A effects,as observed in a study with IDO patients [Kuo et al.,2007].

In IDO patients the commonest complication is urinaryretention. When injecting 200 U of Botox® a 20-30%rate of prolonged urinary retention might be expectedwhich will require prolonged clean intermittentcatheterization to ensure bladder emptying [Kuo et al.,2004; Popat et al., 2005|; Kuo et al., 2005; Sahai etal., 2007]. Open-label trials which used lower doses(100 U of Botox®) reported a lower incidence of thiscomplication [Schmid et al., 2006; Kuo et al., 2007].

Although it is a concern frequently raised, at thismoment there is no evidence that repeated BONT-Ainjections cause detrusor atrophy or bladder wallfibrosis. Whether Dysport® or Botox® was usedrepeated injections in NDO patients in the short tomedium term did not decrease bladder compliance,which would presumably be the case if fibrosis wereto develop [Del Popolo et al., 2008; Reitz et al., 2007].

Histological inspection of injected bladders did notshow inflammatory changes, fibrosis, or dysplasiaafter repeated treatments and independently of theneurogenic or non-neurogenic origin of the detrusoroveractivity [Haferkamp et al., 2004; Compérat et al.,2006; Apostolidis et al., 2008]. Rather the reverse,one study demonstrated that NDO patients treated withBONT-A had less fibrosis than nontreated patients[Compérat et al., 2006]. Curiously, the presence ofeosinophilic infiltrate was shown to increase inspecimens of patients receiving multiple treatments,a finding that could not be fully explained [Apostolidiset al., 2008].

i) Cost-effectiveness of BONT-A in NDO patients

Economic aspects of BONT-A are a concern due tothe price of the drug and the need for repeatedcystoscopies, very often performed under generalanaesthesia and under close monitoring to detectand treat eventual episodes of autonomic dysreflexia.Nevertheless, In UK, in a cohort of 101 patients withdetrusor overactivity, 63 of whom of neurogenic origin,BONT-A treatment was shown to be cost-effective inboth NDO and IDO cases [Kalsi et al., 2006].

Costs were based on the resources used by typicalpatients in UK and in the cost-effectiveness of 200-300 U BONT-A (Botox®) compared with standardcare [Kalsi et al., 2006]. In Germany BONT-A (Botox®)treatment halved costs for incontinence aids and forurinary tract infection treatment in 214 NDO patients[Boy et al., 2008].

j) BONT-B

Some humans repeatedly injected with BONT-A maydevelop resistance to the toxin, possibly due toantibody formation. Although this event seems veryrare in the case of bladder injections, a minimuminterval of three months between two BONT-Ainjections is generally recommended to decrease itsoccurrence. If resistance appears, recent reports[Dykstra et al., 2003; Pistolesi et al,, 2004; Reitz et al.,2004] investigated the replacement of BONT-Aserotype by BONT-B. At this moment, empiric dosesof BONT-B are being used, as there are no clearpotency equivalents for the two serotypes and betweenBONT-B brands.

In three patients with spinal NDO, bladder injection of5000 UI [Pistolesi et al., 2004] or 7500 UI [Reitz andSchurch, 2004] of BONT-B (Neurobloc®) restoredbladder function for six months [Reitz and Schurch,2004]. Interestingly, one patient experienced dry mouthand dry eyes that resolved within 20 days. As thisside effect was not reported after bladder BONT-Aapplication, it is possible that different toxin serotypeshave some different degrees of organ affinity. Dykstraet al. [2003] carried on a dose escalation study withBONT-B (Miobloc®) in 15 female patients with OAB.They used doses of 2500, 3750, 5000, 10,000, and15,000 U injected at 10 sites. Only one patient failedto respond, and a clear dose-dependent effect wasobserved, with the longest response seen in thoseinjected with 15,000 U. Two patients, both injected with15,000 U, experienced dry mouth and general malaise.In another study involving IDO and NDO patients, inwhich BONT-B (Neurobloc®) 5000 U were used, Hirstand coworkers [2007] observed a limited duration ofaction, with most of the symptomatic beneficial effectswearing off by 10 weeks in most of the patients. Theshort duration of action for BONT-B at safe dosesmay, therefore, limit the clinic usefulness of thisserotype.

2. CAPSAICIN AND RESINIFERATOXIN (RTX)

a) Rationale for intravesical vanilloids

The rationale for intravesical vanilloid application inpatients with DO was offered by the demonstration thatcapsaicin, following bladder C-fiber desensitization,suppresses involuntary detrusor contractionsdependent upon a sacral micturition reflex [de Groatet al., 1997]. The C-fiber micturition reflex is usuallyinactive but it was shown that it is enhanced in patientswith chronic spinal-cord lesions above sacral segments[de Groat et al., 1997] in those with chronic bladderoutlet obstruction [Chai et al., 1998] and in those with

IDO [Silva et al., 2002]. In the bladders of NDOpatients, the enhancement of the micturition reflex isaccompanied by an increase in the number of sub-urothelial C-fibers expressing TRPV1 [Brady et al.,2004]. Curiously, NDO patients who responded better

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to intravesical RTX exhibited a significant decreasein the density of TRPV1 immunoreactive fibers,whereas non-responders experience a non-significantvariation [Brady et al., 2004]. A decrease in TRPV1expression in urothelial cells of NDO patients wasalso demonstrated after intravesical application ofRTX [Apostolidis et al., 2005].

Changes in sub-urothelial C-fiber innervationexpressing neuropeptides [Smet et al., 1997] or TRPV1[Liu et al., 2007] were also reported in patients withsensory urgency. In IDO patients, responders tointravesical RTX are closely associated with the over-expression of the receptor in the bladder mucosa [Liuet al., 2007]. In women with sensory urgency, TRPV1mRNA expressed in trigonal mucosa was not onlyincreased but also inversely correlated with the bladdervolume at first sensation of filling during cystometryfurther indicating that TRPV1 plays a role in prematurebladder sensation [Liu et al., 2007].

b) Intravesical capsaicin

Intravesical capsacin for NDO was studied in six non-controlled [Fowler et al., 1992; Fowler et al., 1994;Geirsson et al., 1995; Das et al., 1996; Igawa et al.,1996, Cruz et al., 1997, De Ridder et al., 1997] and1 controlled clinical trial [de Seze et al., 1998].Capsaicin was dissolved in 30% alcohol and 100-125ml (or half of the bladder capacity if lower than thatvolume) of 1-2 mM solutions were instilled into thebladder and left in contact with the mucosa for 30minutes. Best clinical results were found amongpatients with incomplete spinal cord lesions, in whomclinical improvement could be observed in up to 70-90% the patients [Fowler et al., 1994, Cruz et al.,1997; De Ridder et al., 1997]. In patients with completespinal cord lesions the success rate was much lower[Geirsson et al., 1995].

Only one small randomized controlled study comparedcapsaicin against 30% ethanol, the vehicle solution.Ten patients received capsaicin and found a significantregression of the incontinence and urge sensation. Incontrast, only 1 among the 10 patients that receivedethanol had clinical improvement [de Seze et al.,1998].

The pungency of alcoholic capsaicin solutions hasprevented the widespread use of this compound. Inparticular, the possibility of triggering autonomicdysreflexia with capsaicin, especially in patients withhigher spinal cord lesions has progressively restrainedits use. The relevance of capsaicin might howeverbe back with a recent observation by de Séze et al.[2006] with a new capsaicin formulation. Theyconducted a double blind placebo controlled studywith a glucidic solution of capsaicin in 33 NDO patients.The glucidic-capsaicin treated group showedimprovement both in symptoms and urodynamicparameters above the comparator arm [de Sèze et al.,

2006]. The global tolerance of this new capsaicinformulation was excellent.

c) RTX in NDO

Resiniferatoxin (RTX) has the advantage overcapsaicin in being much less pungent [Cruz et al.,1997]. Intravesical RTX application in NDO patientswas evaluated in five small open-label studies [Cruzet al., 1997; Kuo, 2003; Lazzeri et a., 1997; Lazzeriet al., 1998; Silva et al., 2000]. Different RTXconcentrations, 10 nM, 50 nM, 100 nM and 10 µM weretested. RTX brought a rapid improvement ordisappearance of urinary incontinence in up to 80%of the selected patients and a 30% decrease in theirdaily urinary frequency.

Furthermore, RTX also increased the volume to firstdetrusor contraction and maximal cystometric capacity.In general, in patients receiving 50-100 nM RTX theeffect was long-lasting, with a duration of more thansix month being reported. In patients treated with 10µM doses, transient urinary retention may occur[Lazzeri et al., 1998].

In a recent placebo-controlled study, the urodynamiceffects of RTX in NDO patients were specificallyevaluated. Only in the RTX arm was a significantincrease in first detrusor contraction and maximalcystometric capacity found [Silva et al., 2005]. RTXalso caused a significant improvement in urinaryfrequency and incontinence [Silva et al., 2005].

RTX, 600 nM was compared against BONT-A (Botox®,300U) in a study involving 25 patients with NDO dueto chronic spinal cord injury. Both neurotoxins werecapable of significantly reducing the number of dailyincontinence episodes and improving maximumbladder capacity, although BONT-A turned out to bemore effective [Giannantoni et al., 2004].

d) RTX in IDO

The first study with intravesical RTX in IDO patientswas designed as a proof-of-concept study and involved13 patients. Intravesical RTX 50 nmol/L was associatedwith an improvement in volume to FDC from 170 ± 109mL to 440 ± 153 mL at 30 days, and to 391 ± 165 mLat 90 days. An increase in mean MCC from 291 ±160 mL to 472 ± 139 mL at 30 days and to 413 ± 153mL at 90 days was also observed (Figure 14). Theseimprovements were accompanied by a decrease inepisodes of urgency incontinence and of dailyfrequency [Silva et al., 2002]. Subsequent small openlabel studies confirmed these observations usingeither a single high (50-100 nM) or multiple low (10nM) dose approaches [Kuo et al., 2003; Dinis et al.,2004; Kuo et al., 2005].

The effect of RTX on refractory IDO was evaluated intwo randomized clinical trials. One, involved 54 patientsrandomized to receive four weekly instillations of a lowconcentration RTX solutions (10 nmol/L) or the vehicle

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solution, 10% ethanol in saline [Kuo et al., 2006] Threemonths after completing the four intravesicaltreatments, the RTX treated group had 42.3% and19.2% of patients feeling much better or improved,respectively. This was significantly more than in theplacebo group, 14.2% and 7.1% respectively. At sixmonths treatment remained effective in 50% patientsin the RTX group but only in 11% in the placebo group[Kuo et al., 2006]. Such clinical and urodynamicfindings could not be reproduced in another study inwhich patients were randomly assigned to receive asingle intravesical dose of 100 ml of either RTX 50 nMor placebo. Patients were followed-up only for fourweeks. During this period a single 50 nM intravesicaldose of RTX was not better than placebo for thetreatment of women with IDO and urgencyincontinence [Rios et al., 2007].

e) RTX and urgency

The involvement of bladder C-fibers in IDO has ledsome investigators to explore the role of these sensoryafferents to the genesis of urgency. In a non-controlledstudy involving 12 male patients with LUTS associatedwith benign prostate enlargement (BPE), meanInternational Prostate Symptom Scores (IPSS) halvedfollowing intravesical administration of RTX (50nmol/L). The decrease in IPSS was largely due toimprovements in scores related to urgency, in additionto improvement in nocturia and frequency [Dinis et al.,2005]. In another open-label study 15 patients withintractable urgency and frequency, with or withouturgency incontinence or bladder pain/discomfort, andwithout urodynamic evidence of DO received onesingle 50 nM RTX solution. A trend towards animprovement of urgency was noticed [Apostolidis etal., 2006]. In a more recent study involving first aplacebo instillation and one month later a 50 nM RTXadministration to 23 patients with refractory urgency,a significant decrease in the number of episodes ofurgency were detected after RTX treatment whencompared with the placebo treatment [Silva et al.,2007].

At the moment and probably in the near future, a lackof stable preparations of RTX available for easybladder instillation will make further investigation of thecompound difficult. Different origins of the vanilloidand different ways for preparation and storage of thesolutions might have caused substantial differencesin the amount of active compound effectivelyadministered to the patients. In addition, RTX adheresto plastics, another reason to the enormousdiscrepancies have been observed among RTXstudies, with some claiming good results and othersnot demonstrating any superiority of RTX over placebo.Development of new, user-friendly formulations isneeded.

Capsaicin and RTX will also face the concurrence ofsmall molecule TRPV1 antagonists that act as a

blockade of TRPV1 receptors rather than desensitizingthem. Some of these compounds are already enteringpreliminary clinical trials. The interested reader mightfind an extensive review on small molecule TRPV1antagonists elsewhere [Szallasi et al., 2006]. Veryrecently an experimental study was presented showingthat one of these compounds (GRC 6211) active byoral route could reduce frequency of bladder reflexcontractions as well as spinal c-fos expression in ratmodels of cystitis (Figure 15). Interestingly in theoptimal therapeutic doses, this TRPV1 antagonisthad no effect on the bladder activity of intact animals[Cruz et al., 2008; Charrua et al., 2008].

1. BACLOFEN

Gamma-amino-butyric acid (GABA) is a ubiquitousinhibitory neurotransmitter in the CNS that can inhibitthe micturition reflex in several points along its centralpathway [De Groat, 1997; Pehrson et al., 2002]. Asa GABA agonist on GABA(B) receptors, baclofen wasused orally in IDO patients. However, its efficacy waspoor, eventually dictated by the fact that baclofendoes not cross the blood-brain barrier [Taylor andBates, 1979]. To overcome this inconvenience,intrathecal baclofen was shown to be useful in somepatients with spasticity and bladder dysfunction[Bushman et al., 1993]. Baldo et al. [2000] could finda rapid (24 hours) and persistent increment in thevolume to first detrusor contraction and of the maximalcystometric whereas maximal detrusor pressuredecreased. At ten days the volume to first detrusorcontraction had increased from 143 ml to 486 ml.Contrasting with the limited published clinicalexperience, some recent experimental data may revivethe GABAergic system as a target for bladderdysfunction therapy. Baclofen intrathecally attenuatedoxyhemoglobin induced detrusor overactivity,suggesting that the inhibitory actions of GABA(B)receptor agonists in the spinal cord may be useful forcontrolling micturition disorders caused by C-fiberactivation in the urothelium and/or suburothelium[Pehrson et al, 2002]. In spinally intact rats, intrathecalapplication of bicuculline induced detrusor-sphincterdyssynergia (DSD)-like changes whereas intrathecalapplication of baclofen induces urethral relaxationduring isovolumetric bladder contractions. Theseresults indicate not only that GABA receptor activationin the spinal cord exerts inhibitory effects on DSDafter SCT but also that decreased activation ofGABA(A) receptors due to hypofunction of GABAergicmechanisms in the spinal cord might be responsibleat least in part for the development of DSD after spinalcord transaction (SCT) [Miyazato et al., 2008a]. Thesefindings are reinforced by the observation thatglutamate decarboxylase 67 mRNA levels in the spinalcord and dorsal root ganglia were decreased after

X. OTHER DRUGS

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Figure 14 : Effect of intravesical resiniferatoxin in patients with idiopathic DO

Figure 15 : Effects of the TRPV1 receptor antagonists, GRC-6211, on rat spinal c-fos expression induced byinstillation of acetic acid into the bladder. Unpublished information, courtesy F. Cruz

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spinal cord transection. Therefore, stimulation of spinalGABAergic mechanisms can be useful for thetreatment of detrusor overactivity after spinal cordinjury [Miyazato et al., 2008b]. For assessment, seeTable 2.

Combining the current α1-AR antagonists with otheragents might theoretically provide improved symptomrelief. One such example is the combination of α1-ARantagonists with 5-α reductase inhibitors, which hasproven to improve clinical outcomes and reduce theincidence of BPH and LUTS progression measuredas symptom worsening, retention or progression tosurgery [McConnell et al., 2003, Roehrborn et al.,2008]. Other combinations have also been tested withvarying degrees of success. Traditionally muscarinicreceptor antagonists have been contraindicated inpatients with BPH due to fears of urinary retention.However, this dogma has been questioned and severalstudies have been performed in which α1-ARantagonists are combined with muscarinic receptorantagonists with promising results [Athanasopouluset al., Lee et al., 2004; 2005; 2008; Ruggieri et al,2006; Kaplan et al., 2006; Novara et al., 2006; McVary, 2007; Rovner et al., 2008]. Speculatively, severalother combinations can be suggested [Andersson,2008].

1. PERIPHERALLY ACTING DRUGS

a) Vitamin D3 receptor analogues

Rat and human bladders were shown to expressreceptors for vitamin D [Crescioli et al., 2005], whichmakes it conceivable that the bladder may also be atarget for vitamin D. Analogues of vitamin D3 have alsobeen shown to inhibit benign prostatic hyperplasia(BPH) cell proliferation and to counteract the mitogenicactivity of potent growth factors for BPH cells [Crescioliet al., 2002; 2003; 2004]. Experiments in rats withbladder outflow obstruction [Schröder et al., 2006]showed that one of the analogues, BXL-628(elocalcitol), at non-hypercalcemic doses, did notprevent bladder hypertrophy, but reduced the decreasein contractility of the bladder smooth muscle whichoccurred with increasing bladder weight [Schröder etal., 2006]. The mechanism of action for the effects hasnot been clarified. However, elocalcitol was shown tohave an inhibitory effect on the RhoA/Rho kinasepathway [Morelli et al., 2007]. Upregulation of hispathway has been associated with bladder changesassociated with diabetes, outflow obstruction, andDO [Peters et al., 2006; Christ and Andersson, 2007].The effect of elocalcitol on prostate volume was

evaluated in patients with BPH, and it was found thatelocalcitol was able to arrest prostate growth within12 weeks in men aged>or=50 years with prostaticvolume > or = 40 ml [Colli et al., 2006]. In an RCTenrolling 120 female patients with OAB, where theprimary endpoint was an increase in the mean volumevoided, a significant increase vs placebo (22% vs11%) was demonstrated [Colli et al., 2007]. Whetheror not vitamin D receptor agonism (monotherapy orin combination) will be a useful alternative for thetreatment of LUTS/OAB, requires further RCTs.

2. CENTRALLY ACTING DRUGS

Many parts of the brain seem to be activated duringstorage and voiding [see, Griffiths 2007; Fowler etal., 2008; Griffiths and Tadic, 2008], and there isincreasing interest in drugs modulating the micturitionreflex by a central action [Andersson and Pehrson,2003]. Several drugs used for pain treatment alsoaffect micturition; morphine and some antiepilepticdrugs being a few examples. However, central nervousmechanisms have so far not been preferred targetsfor drugs aimed to treat OAB, since selective actionsmay be difficult to obtain. Holstege [2005], reviewingsome of the central mechnisms involved in micturition,including the periaqueductal gray (PAG) and thepontine micturition center (PMC), suggested that “theproblem in OAB or urgency-incontinence is at thelevel of the PAG or PMC and their connections, andpossible treatments for this condition should targetthe micturition pathways at that level.”

a) Gonadotropin-releasing hormone antagonists

The beneficial effects of the 5α-reductase inhibitors,finasteride and dutasteride in the treatment of maleLUTS are well documented. The efficacy of otherhormonal treatments, for example, antiandrogens orgonadotropin-releasing hormone (GNRH; also knownas luteinizing hormone-releasing hormone: LHRH)agonists is either poor or at the expense ofunacceptable side effects such as medical castrationassociated with hot flushes, decrease of potency andlibido, and negative effects on bone density followinglong-term androgen ablation [Schroeder et al. 1986;Peters et al 1987; Bosch et al., 1989; Eri and Tveter,1993]. With LHRH antagonists submaximal, non-castrating blockade of the androgen testosterone andconsequently of dihydrotestosterone (DHT) can beachieved, thus avoiding medical castration.

Debruyne et al. [2008] demonstrated in a phase 2RCT that the LHRH antagonist cetrorelix, givensubcutaneously weekly for 20 weeks to 140 men withLUTS (IPSS > 13, peak urinary flow rates 5-13 ml/s),rapidly caused a significant improvement in the meanIPSS: the peak decrease was -5.4 to -5,9 vs -2,8 forplacebo. All dosage regimens tested were welltolerated, and the authors concluded that the drug

XII. FUTURE POSSIBILITIES

XI. COMBINATIONS

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offered a safe and effective treatment of male LUTS.Further studies are needed to assess whether or notthis therapeutic principle is a useful addition to thecurrent treatment alternatives.

b) Gabapentin

Gabapentin is one of the new first-generationantiepileptic drugs that expanded its use into a broadrange of neurologic and psychiatric disorders [Strianoand Striano 2008]. It was originally designed as ananticonvulsant GABA (y-aminobutyric acid) mimeticcapable of crossing the blood-brain barrier [Maneufet al., 2003]. The effects of gabapentin, however, donot appear to be mediated through interaction withGABA receptors, and its mechanism of action remainscontroversial [Maneuf et al., 2003]. It has beensuggested that it acts by binding to a subunit of theα2δ unit of voltage dependent calcium channels [Geeet al., 1996; Striano and Striano, 2008]. Gabapentinis also widely used not only for seizures andneuropathic pain, but for many other indications, suchas anxiety and sleep disorders, because of its apparentlack of toxicity.

Carbone et al. [2006] reported on the effect ofgabapentin on neurogenic DO. They found a positiveeffect on symptoms and significant improvement inurodynamic parameters, and suggested that the effectsof the drug should be explored in further controlledstudies in both neurogenic and non-neurogenic DO.Kim et al. [2004] studied the effects of gabapentin inpatients with OAB and nocturia not responding toantimuscarinics. They found that 14 out of 31 patientsimproved with oral gabapentin. The drug was generallywell tolerated, and the authors suggested that it canbe considered in selective patients when conventionalmodalities have failed. It is possible that gabapentinand other α2δ ligands (e.g., pregabalin and analogs)

will offer new therapeutic alternatives.

c) Tramadol

Tramadol is a well-known analgesic drug [Grond andSablotzski, 2004]. By itself, it is a weak µ-receptoragonist, but it is metabolized to several differentcompounds, some of them almost as effective asmorphine at the µ-receptor. However, the drug(metabolites) also inhibits serotonin (5-HT) andnoradrenaline reuptake [Grond and Sablotzski, 2004].This profile is of particular interest, since both µ-receptor agonism and amine reuptake inhibition maybe useful principles for treatment of LUTS/OAB/DO,as shown in a placobo controlled study with duloxetine[Steers et al., 2008].

In rats, tramadol abolished experimentally inducedDO caused by cerebral infarction [Pehrson et al.,2003]. Tramadol also inhibited DO induced byapomorphine in rats [Pehrson and Andersson, 2003]– a crude model of bladder dysfunction in Parkinson´sdisease. Singh et al. [2008] gave tramadol epidurally

and found the drug to increase bladder capacity andcompliance, and to delay filling sensations withoutadverse effects on voiding. Safarinejad and Hosseini[2006] evaluated in a double-blind, placebo-controlled,randomized study, the efficacy and safety of tramadolin patients with idiopathic DO. A total of 76 patients18 years or older were given 100 mg tramadolsustained release every 12 h for 12 weeks. Clinicalevaluation was performed at baseline and every twoweeks during treatment. Tramadol significantly (p<001)reduced the number of incontinence periods per 24hours from 3.2±3.3 to 1.6±2.8) and inducedimprovements in urodynamic parameters. The mainadverse event was nausea. It was concluded that inpatients with non-neurogenic DO, tramadol providedbeneficial clinical and urodynamic effects. Even iftramadol may not be the best suitable drug fortreatment of LUTS/OAB, the study suggests efficacyfor modulation of micturition via the µ-receptor.

d) NK1-receptor antagonists.

The main endogenous tachykinins, substance P (SP),neurokinin A (NKA) and neurokinin B (NKB), and theirpreferred receptors, NK1, NK2, and NK3, respectively,have been demonstrated in various CNS regions,including those involved in micturition control [Lecciand Maggi, 2001; Saffroy et al., 2003; Covenas etal., 2003]. NK1 receptor expressing neurons in thedorsal horn of the spinal cord may play an importantrole in DO, and tachykinin involvement via NK1receptors in the micturition reflex induced by bladderfilling has been demonstrated [Ishizuka et al., 1994]in normal, and more clearly, rats with bladderhypertrophy secondary to BOO. Capsaicin-induceddetrusor overactivity was reduced by blocking NK1receptor-expressing neurons in the spinal cord, usingintrathecally administered substance P-saponinconjugate [Seki et al., 2002]. Furthermore, blockadeof spinal NK1 receptor could suppress detrusor activityinduced by dopamine receptor (L-DOPA) stimulation[Ishizuka et al., 1995a].

In conscious rats undergoing continuous cystometry,antagonists of both NK1 and NK2 receptors inhibitedmicturition, decreasing micturition pressure andincreasing bladder capacity at low doses, and inducingdribbling incontinence at high doses. This was mostconspicuous in animals with outflow obstruction [Guet al., 2000]. Intracerebroventricular administrationof NK1 and NK2 receptor antagonists to awake ratssuppressed detrusor activity induced by dopaminereceptor (L-DOPA) stimulation [Ishizuka et al., 2000].Taken together, available information suggests thatspinal and supraspinal NK1 and NK2 receptors maybe involved in micturition control.

Aprepitant, an NK-1 receptor antagonist used fortreatment of chemotherapy-induced nausea andvomiting [Massaro and Lenz, 2005], significantlyimproved symptoms of OAB in postmenopausalwomen with a history of urgency incontinence or mixed

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incontinence (with predominantly urgency urinaryincontinence), as shown in a well designed pilot RCT[Green et al., 2006]. The primary end point was percentchange from baseline in average daily micturitionsassessed by a voiding diary. Secondary end pointsincluded average daily total urinary incontinence andurgency incontinence episodes, and urgency episodes.Aprepitant significantly (p<0.003) decreased theaverage daily number of micturitions (-1.3±1.9)compared with placebo (-0.4±1.7) at 8 weeks. Theaverage daily number of urgency episodes was alsosignificantly (p<0.047) reduced (-23.2±32%) comparedto placebo (-9.3±40%), and so were the average dailynumber of urgency incontinence and total urinaryincontinence episodes, although the difference wasnot statistically significant. Aprepitant was generallywell tolerated and the incidence of side effects,including dry mouth, was low. The results of this initialproof of concept study suggest that NK-1 receptorantagonism holds promise as a potential treatmentapproach for OAB.

Many factors seem to be involved in the pathogenesisof stress urinary incontinence (SUI): urethral support,vesical neck function, and function of the nerves andmusculature of the bladder, urethra, and pelvic floor[DeLancey, 1997; Mostwin et al., 2005]. Anatomicalfactors cannot be treated pharmacologically. However,women with SUI have lower resting urethral pressuresthan age-matched continent women [Henriksson et al,1979; Hilton et al, 1983], and since it seems likelythat there is a reduced urethral closure pressure inmost women with SUI, it seems logical to increaseurethral pressure to improve the condition.

Factors which may contribute to urethral closureinclude tone of urethral smooth and striated muscleand the passive properties of the urethral laminapropria, in particular its vasculature. The relativecontribution to intraurethral pressure of these factorsis still subject to debate. However, there is amplepharmacological evidence that a substantial part ofurethral tone is mediated through stimulation of α-ARs in the urethral smooth muscle by releasednoradrenaline [Andersson, 1993; Andersson and Wein,2004]. A contributing factor to SUI, mainly in elderlywomen with lack of estrogen, may be lack of mucosalfunction. The pharmacological treatment of SUI aimsat increasing intraurethral closure forces by increasingthe tone in the urethral smooth and striated muscles.Several drugs may contribute to such an increase[Andersson, 1988; Zinner et al., 2004], but relativelack of efficacy or/and side effects have limited theirclinical use. For assessments, see Table 4.

Several drugs with agonistic effects on α-ARs havebeen used in the treatment of SUI (Table 4). However,ephedrine and norephedrine (phenylpropanolamine;PPA) seem to have been the most widely used[Andersson et al., 2002]. The original Agency forHealthcare Policy and Research Guidelines (Agencyfor Healthcare Policy and Research, 1992) reported8 randomized controlled trials with PPA, 50 mg twicedaily for SUI in women. Percent cures (all figuresrefer to percent effect on drug minus percent effect onplacebo) were listed as 0% to 14%, percent reductionin continence as 19% to 60%, and percent side effectsand percent dropouts as 5% to 33% and 0% to 4.3%respectively. The most recent Cochrane review onthe subject [Alhasso et al., 2005] assessed randomizedor quasi-randomized controlled trials in adults withstress urinary incontinence which included anadrenergic agonist drug in at least one arm of thetrial. There were no controlled studies reported onthe use of such drugs in men. Twenty-two eligibletrials were identified, 11 of which were crossover trials,which included 1099 women, 673 of whom receivedan adrenergic drug (PPA in 11, midrodrine in two,norepinephrine in three, clenbuterol in three, terbutalinein one, eskornade in one and RO 115-1240 in one).The authors concluded “there was weak evidence tosuggest that use of an adrenergic agonist was betterthan placebo treatment”. The limited evidencesuggested that such drugs were better than placeboin reducing the number of pad changes andincontinence episodes, and in improving subjectivesymptoms. There was not enough evidence toevaluate the merits of an adrenergic agonist comparedwith estrogen, whether used alone or in combination.

I. αα-ADRENCEPTOR AGONISTSC. DRUGS USED FORTREATMENT OF STRESSURINARY INCONTINENCE

Table 4. Drugs used in the treatment of stressincontinence. Assessments according to theOxford system (modified)

Drug Level of Grade of evidence recommendation

Duloxetine 1 B

Imipramine 3 D

Clenbuterol 3 C

Methoxamine 2 D

Midodrine 2 C

Ephedrine 3 D

Norephedrine(phenylpropanolamine) 3 D

Estrogen 2 D

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Regarding adverse events, the review reported similarnumbers with adrenergic, placebo, or alternative drugtreatment. Over 25% of subjects reported such effects,but when these consisted of effects due to adrenergicstimulation, they caused discontinuation in only 4 %of the total.

The date of the most recent amendment to this reviewis listed as 15 May 2007; no new trials were identifiedat that time. The update of 2005 [Alhasso et al., 2005]included seven new randomized controlled trials overthe 2003 report, cited in the last consultation. Thefinal statement on “what’s new” reads, “Theconclusions still provide limited support for the use ofadrenergics but side effects may cause dropout, andsome side effects may be dangerous. Further trials areneeded”.

Ephedrine and PPA lack selectivity for urethral α-ARsand can increase blood pressure and cause sleepdisturbances, headache, tremor, and palpitations[Andersson et al., 2002]. Kernan et al. [2000] reportedthe risk of hemorrhagic stroke to be 16 times higherin women less than 50 years of age who had beentaking PPA as an appetite suppressant (statisticallysignificant) and 3 times higher in women who hadbeen taking the drug for less than 24 hours as a coldremedy (not statistically significant). There was noincreased risk in men. PPA has been removed fromthe market in the United States.

Numerous case reports of adverse reactions due toephedra alkaloids exist, and some [Bent et al., 2003]had suggested that sale of these compounds as adietary supplement be restricted or banned. InDecember 2003, the Food and Drug Administrationof the US decreed such a ban, a move which hassurvived legal appeal.

Midodrine and methoxamine stimulate α1-ARs withsome degree of selectivity. According to the RCTsavailable, the effectiveness of these drugs is moderateand the clinical usefulness seems to be limited byadverse effects [Alhasso et al., 2003; Radley et al.,2001; Weil et al., 1998].

Attempts continue to develop agonists with relativeselectivity for the human urethra. Musselman et al.[2004] reported on a phase two randomized crossoverstudy with Ro 115-1240, a peripheral active selectiveα-1A/L-AR adrenoceptor partial agonist [Blue et al.,2004] in 37 women with mild to moderate SUI. Amoderate, positive effect was demonstrated, but sideeffects have apparently curtailed further developmentof the drug.

The theoretical basis for the use of ß-AR antagonistsin the treatment of stress incontinence is that blockadeof urethral ß-ARs may enhance the effects ofnoradrenaline on urethral α-ARs. Propranolol has

been reported to have beneficial effects in thetreatment of stress incontinence [Gleason et al., 1974;Kaisary, 1984] but there are no RCTs supporting suchan action. In the Gleason et al. [1974] study thebeneficial effects become manifest only after 4 to 10weeks of treatment; a phenomenon difficult to explain.Donker and Van der Sluis [1976] reported that ß-blockade did not change UPP in normal women.Although suggested as an alternative to ß-AR agonistsin patients with SUI and hypertension, these agentsmay have major potential cardiac and pulmonary sideeffects of their own, related to their therapeutic ß-ARblockade.

ß-AR stimulation is generally conceded to decreaseurethral pressure [Andersson, 1993], but ß2-ARagonists have been reported to increase thecontractility of some fast contracting striated musclefibers and suppress that of slow contracting fibers ofothers [Fellenius et al., 1980]. Some ß-AR agonistsalso stimulate skeletal muscle hypertrophy – in fasttwitch more so than slow twitch fibers [Kim et al.,1992]. Clenbuterol has been reported to potentiate thefield stimulation induced contraction in rabbit isolatedperiurethral muscle preparations, an action which issuppressed by propanolol and greater than thatproduced by isoprotererol [Kishimoto et al., 1991].These authors were the first to report an increase inurethral pressure with clinical use of clenbuterol andto speculate on its potential for the treatment of SUI.Yaminishi et al. [1994] reported an inotropic effect ofclenbuterol and terbutaline on the fatigued striatedurethral sphincter of dogs, abolished by ß-ARblockade.

Yasuda et al. [1993] described the results of a doubleblind placebo controlled trial with this agent in 165women with SUI. Positive statistical significance wasachieved for subjective evaluation of incontinencefrequency, pad usage per day, and overall globalassessment. Pad weight decreased from 11.7± 17.9g to 6.0± 12.3 g for drug and from 18.3± 29.0 g to 12.6±24.7 g for placebo, raising questions about thecomparability of the 2 groups. The “significant” increasein maximum urethral closure pressure (MUCP) wasfrom 46.0± 18.2 cm H2O to 49.3± 19.1 cm H2O,versus a change of -1.5 cm H2O in the placebo group.56/77 patients in the clenbuterol group reported somedegree of improvement versus 48/88 in the placebogroup. The positive effects were suggested to be aresult of an action on urethral striated muscle and/orthe pelvic floor muscles. Ishiko et al. [2000] investigatedthe effects of clenbuterol on 61 female patients withstress incontinence in a 12-week randomized study,comparing drug therapy to pelvic floor exercises. Thefrequency and volume of stress incontinence and thepatient’s own impression were used as the basis for

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the assessment of efficacy. The improvement ofincontinence was 76.9%, 52.6%, and 89.5% in therespective groups. In an open study, Noguchi et al.[1997] reported positive results with clenbuterol (20mg twice daily for one month) in nine of 14 patientswith mild to moderate stress incontinence after radicalprostatectomy. No subsequent published reports haveappeared. Further well-designed RTCs documentingthe effects of clenbuterol are needed to adequatelyassess its potential as a treatment for stressincontinence.

1. IMIPRAMINE

Imipramine, among several other pharmacologicaleffects, inhibits the re-uptake of noradrenaline andserotonin in adrenergic nerve endings. In the urethrathis can be expected to enhance the contractile effectsof noradrenaline on urethral smooth muscle. Gilja etal [1984] reported in an open study on 30 womenwith stress incontinence that imipramine, 75 mg daily,produced subjective continence in 21 patients andincreased mean maximal urethral closure pressure(MUCP) from 34 to 48 mm Hg. A 35% cure rate wasreported by pad test and, in an additional 25%, a 50%or more improvement.

Lin et al. [1999] assessed the efficacy of imipramine(25 mg imipramine three times a day for three months)as a treatment in 40 women with genuine stressincontinence. A 20-minute pad test, uroflowmetry,filling and voiding cystometry, and stress urethralpressure profile were performed before and aftertreatment. The efficacy of “successful treatment” was60% (95% CI 11.8-75.2). There are no RCTs on theeffects of imipramine on SUI. No subsequent publishedreports have appeared.

2. DULOXETINE

As mentioned previously, duloxetine is a combinedserotonin and noradrenaline reuptake inhibitor, whichhas been shown to significantly increase sphinctericmuscle activity during the filling/storage phase ofmicturition in the cat acetic acid model of irritatedbladder function [Thor et al., 1995; Katofiasc et al.,2002]. The sphincteric effects were reversed by α1-AR (prazosin) and 5HT2 serotonergic (LY 53857)receptor antagonism, while the bladder effects weremediated by temporal prolongation of the actions ofserotonin and noradrenaline in the synaptic cleft(Figure 16) (Fraser et al, 2003). Duloxetine is lipophilic,well absorbed, and extensively metabolized (CYP2D6).Its plasma half-life is approximately 12 hours [Sharmaet al., 2000].

There are many studies, including RCTs, documentingthe effects of duloxetine in SUI [Norton et al., 2002;

Dmochowski et al., 2003; Millard et al., 2004; VanKerrebroeck et al., 2004; Cardozo et al., 2004; Kinchenet al., 2005; Ghoneim et al., 2005; Hurley et al., 2006;Castro-Diaz et al., 2007; Bump, 2008]. A Cochranereview of the effects of duloxetine for stress urinaryincontinence in women is available, the last substantiveamendment listed as 25 May 2005 [Mariappan et al.,2005]. Fifteen reports were deemed eligible foranalysis, nine primary studies and six additional reportsrelated to one or two of the primary references. Anadditional analysis “performed under the auspices ofthe Cochrane Incontinence Group” was performedon just the nine primary trials comparing duloxetineand placebo, and published separately [Mariappanet al., 2007]. The results can be summarized as follows.Subjective “cure” in the duloxetine 80 mg daily (40 mgtwice daily) was higher than in the placebo group(10.8 % vs 7.7%, overall relative risk (RR) = 1.42;95% confidence interval (CI), 1.02-1.98; p = 0.04).The estimated absolute size of effect was about threemore patients cured of every 100 treated. Objectivecure data, available from only one trial, showed noclear drug/placebo difference. Duloxetine showedgreater improvement in I-QoL (weighted meandifference (WMD) for 80 mg: 4.5; 95% CI 2.83-6.18,p < 0.00001). Patient global impression of improvement(PGI-I) data also favored the drug (RR for better healthstatus 1.24, 95% CI 1.14-1.36; p < 0.00001). Adverseeffects in six trials were analyzed. These were reportedby 71% of drug subjects and 59% of those allocatedto placebo. Nausea was the most common adverseevent and the incidence ranged from 23 to 25% andwas the main reason for discontinuation. Other sideeffects reported were vomiting, constipation, dry mouth,fatigue, dizziness and insomnia, overall RR 1.30 (95%CI, 1.23-1.37). Across these six trials 17% in the druggroup withdrew, 4 % in the placebo arm. In the 2007article the authors conclude by saying that furtherresearch is needed as to whether managementpolicies incorporating duloxetine are clinically effectiveand cost effective compared to other current minimallyinvasive and more invasive approaches in patients withvarying severity of SUI, and that “longer termexperience is now a priority to determine whetherthere is sustained efficacy during and after duloxetineuse and to rule out complications”. Hashim and Abrams[2006] suggested that in order to reduce the risk ofnausea, begin with a dose of 20 mg twice daily for twoweeks, then to increase to the recommended 40 mgtwice daily dosage.

Duloxetine is licensed at 40 mg twice daily for thetreatment of SUI in the European Union (EuropeanMedicines Agency, Scientific Discussion, 2005) forwomen with moderate to severe incontinence (definedas 14 or more episodes per week). It was withdrawnfrom the Food and Drug Administration (FDA)consideration process in the United States for thetreatment of SUI, but is approved for the treatment ofmajor depressive disorder (20-30 mg twice daily

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initially, 60 mg once daily maintenance), diabeticperipheral neuropathic pain (60 mg once daily), andgeneralized anxiety disorder (60 mg once daily). Theproduct information contains a “black box” warning of“increased risk of suicidal thinking and behavior inchildren, adolescents and young adults takingantidepressants for major depressive disorder andother psychiatric disorders”, noting also that“depression and certain other psychiatric disordersare themselves associated with increases in the riskof suicide” (Prescribing Information, revised December2007, Eli Lilly and Company, Indianapolis, Indiana46285).

Other warnings and precautions in the United StatesProduct Information for psychiatric indications, notSUI, include hepatotoxicity (not to be used in patientswith substantial alcohol use or chronic liver disease),orthostatic hypotension, serotonin syndrome (generalstatement regarding selective serotonin reuptakeinhibitors (SSRIs) and SNRIs), abrupt discontinuation(may result in dizziness, paresthesias, irritability andheadache), inhibitors of CYP1H2 or thioridazine (donot administer concomitantly), potent inhibitors ofCYP2D6 (may increase concentration), and others.

3. MALE STRESS URINARY INCONTINENCE

Although a problem of significant magnitude, especiallyafter total prostatectomy for cancer, the pharmacologictreatment of male SUI is an area that has receivedrelatively little attention. Tsakiris et al. [2008] searchedfor articles on this subject published between 1966 andJune 2007 and did a generalized database search inaddition. Nine trials were identified using α-ARagonists, ß2-AR antagonists or SNRIs.

Only one of these included a comparison arm[Filocamo et al., 2007], 40 mg twice daily duloxetineplus pelvic floor exercises vs pelvic floor exercises(PFE) with placebo. The results suggested a positiveeffect of drug, but were a bit confusing. Of thosepatients completing the four-month trial (92/112) 78%of the drug treated patients vs 52% of those in theplacebo group were dry. However, one month after theend of the study, the corresponding figures were 46%vs 73%, a shift still observed two months later.

The authors of the review article suggest further largerand well designed studies on duloxetine for thispotential usage.

Figure 16 : Mode of action of duloxetine. The striated urethral sphincter is innervated by the pudendalnerve, which contains the axons of motor neurons whose cell bodies are located in Onuf’s nucleus.Glutamate exerts a tonic excitatory effects on these motor neurons, and this effect is enhanced by nora-drenaline (NA) and serotonin (5-HT), acting on αα1- adrenoceptors and 5-HT2-receptors, respectively. Byinhibition of the reuptake of noradrenaline and serotonin, duloxetine increases the contractile activity in thestriated sphincter (nicotinic receptors: + Nic). DC = dorsal commissure; DH = dorsal horn; VH = ventralhorn; LF = lateral funiculus; ACh = acetylcholine

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Urinary incontinence most often results from too muchpressure generated by the bladder and/or too littleresistance generated by the bladder outflow tractduring the storage phase of the micturition cycle(urgency incontinence and stress urinary incontinence,respectively). More rarely, incontinence can also occurin the presence of too little pressure and/or too muchresistance being developed which can lead to amarkedly distended bladder and urinary retention and,secondarily, to overflow incontinence [Abrams et al.,2002].

Based upon theoretical reasoning, animal studies[Kamo et al., 2005; Gu et al., 2004] or reports of drugswhich can cause overflow incontinence [Anders etal., 1985], a variety of medical approaches to thetreatment of overflow incontinence have beenproposed [Chutka and Takahashi, 1998; Hampel et al.,2005].

These include direct or indirect muscarinic receptoragonists and α1-AR antagonists. The use of the formeris based upon the idea that stimulation of muscarinicreceptors may overcome a hypo-contractile state ofthe detrusor. However, a recent systematic review ofcontrolled clinical studies on the use of direct andindirect parasympathetic agonists in patients with anunderactive detrusor has shown that these drugs donot exhibit consistent benefit and may even be harmful[Barendrecht et al., 2007]. In contrast, the use of α1-AR antagonists has repeatedly been shown tobeneficial in patients with acute urinary retention[McNeill et al., 2004; 2005].

However, neither parasympathomimetic drugs norα1-AR antagonists have ever been tested syste-matically in the treatment of overflow incontinence.Accordingly, a Medline search using the keyword“overflow incontinence” did not yield a singlerandomized controlled trial for its treatment, and noteven a case series with a meaningful number ofpatients was retrieved. Therefore, it must be concludedthat there is no empirical basis to select medicaltreatments for overflow incontinence and all previouslyrecommended treatments must be rated as “expertopinion” at best. Moreover, any medical treatment foroverflow incontinence will have to be evaluated ascompared to catherization or surgery but also for suchcomparison no clinical data are available.

1. ESTROGENS AND THE CONTINENCE MECHANISM

The estrogen sensitive tissues of the bladder, urethraand pelvic floor all play an important role in thecontinence mechanism. For women to remaincontinent the urethral pressure must exceed the intra-vesical pressure at all times except during micturition.The urethra has four estrogen sensitive functionallayers all of which play a part in the maintenance ofa positive urethral pressure 1) epithelium, 2)vasculature, 3) connective tissue, 4) muscle.

Two types of estrogen receptor, (α and β) have beenidentified in the trigone of the bladder, urethra andvagina as well as in the levator ani muscles and fasciaand ligaments within the pelvic floor [Smith et al.,1990; Copas et al., 2001; Gebhardt et al., 2001]. Afterthe menopause, estrogen receptor α has been shownto vary depending upon exogenous estrogen therapy[Fu et al., 2003]. In addition exogenous estrogensaffect the remodeling of collagen in the urogenitaltissues resulting in a reduction of the total collagenconcentration with a decrease in the cross linking ofcollagen in both continent and incontinent women[Falconer et al., 1998; Keane et al., 1997]. Studies inboth animals and humans have shown that estrogensalso increase vascularity in the peri-urethral plexuswhich can be measured as vascular pulsations onurethral pressure profilometry [Robinson et al., 1996;Endo et al., 2000; Versi and Cardozo, 1986].

2. ESTROGENS FOR STRESS URINARYINCONTINENCE

The role of estrogen in the treatment of stress urinaryincontinence has been controversial despite a numberof reported clinical trials [Hextall, 2000]. Some havegiven promising results but this may have beenbecause they were small observational and notrandomized, blinded or controlled. The situation isfurther complicated by the fact that a number ofdifferent types of estrogen have been used with varyingdoses, routes of administration and duration oftreatment. For assessment, see Table 4.

Fantl et al. [1996] treated 83 hypo-estrogenic womenwith urodynamic stress incontinence and/or detrusoroveractivity with conjugated equine estrogens 0.625mg and medroxyprogesterone 10 mg cyclically forthree months. Controls received placebo tablets. Atthe end of the study period the clinical and quality oflife variables did not change significantly in either

I. ESTROGENS

E. HORMONAL TREATMENT OFURINARY INCONTINENCE

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group. Jackson et al. [1996] treated 57 post meno-pausal women with urodynamic stress or mixedincontinence with estradiol 2 mg or placebo daily forsix months. There was no significant change inobjective outcome measures although both the activeand placebo groups reported subjective benefit.

There have been two meta-analyses performed. In thefirst, a report by the Hormones and Urogenital Therapy(HUT) committee the use of estrogens to treat allcauses of incontinence in post menopausal womenwas examined [Fantl et al., 1994]. Of 166 articlesidentified, which were published in English between1969 and 1992, only six were controlled trials and 17uncontrolled series. The results showed that therewas a significant subjective improvement for all patientsand those with urodynamic stress incontinence.However, assessment of the objective parametersrevealed that there was no change in the volume ofurine lost, maximum urethral closure pressureincreased significantly but this result was influencedby only one study showing a large effect.

In the second meta-analysis Sultana and Walters[1990] reviewed eight controlled and 14 uncontrolledprospective trials and included all types of estrogentreatment. They also found that estrogen therapy wasnot an efficacious treatment for stress urinaryincontinence but may be useful for the often associatedsymptoms of urgency and frequency. Estrogen whengiven alone therefore does not appear to be aneffective treatment for stress urinary incontinence.

Several studies have shown that estrogen may havea role in combination with other therapies e.g. α-ARagonists. However, PPA (the most widely used α-ARagonist in clinical practice) has now been restrictedor banned by the US Food and Drug Administration(FDA). In a randomized trial Ishiko et al. [2001]compared the effects of the combination of pelvicfloor exercise and estriol (1 mg per day) in 66 patientswith post meno-pausal stress urinary incontinence.Efficacy was evaluated every three months based onstress scores obtained from a questionnaire. Theyfound a significant decrease in stress score in mild andmoderate stress incontinent patients in both groupsthree months after the start of therapy and concludedthat combination therapy with estriol plus pelvic floorexercise was effective and could be used as first linetreatment for mild stress urinary incontinence.Unfortunately this has not been reproduced in otherclinical trials.

Thus even prior to the more recently reportedsecondary analyses of the heart and estrogens/progestogen replacement study (HERS) [Grady et

al., 2001] and Women’s Health Initiative (WHI) [Hendrixet al., 2005] it was already recognized that estrogentherapy had little effect in the management ofurodynamic stress incontinence [Al-Badr et al., 2003;Robinson and Cardozo, 2003].

3. ESTROGENS FOR URGENCY URINARYINCONTINENCE AND OVERACTIVEBLADDER SYMPTOMS

Estrogen has been used to treat post menopausalurgency and urgency incontinence for many yearsbut there have been few controlled trials to confirm thatit is of benefit [Hextall, 2000; for assessment, seeTable 2]. A double blind multi centre study of 64 postmenopausal women with “urgency syndrome” failedto show efficacy [Cardozo et al., 1993]. All womenunderwent pre-treatment urodynamic investigation toensure that they had either “sensory urgency” or DO.They were randomized to treatment with oral estriol3 mg daily or placebo for three months. Compliancewith therapy was confirmed by a significantimprovement in the maturation index of vaginalepithelial cells in the active but not the placebo group.Estriol produced subjective and objectiveimprovements in urinary symptoms, but was notsignificantly better than placebo.

Another recent randomized controlled trial from thesame group using 25 mg estradiol implants confirmedthe previous findings [Rufford et al., 2003], andfurthermore found a high complication rate in theestradiol treated patients (vaginal bleeding).

Evidence from large clinical trials

The HERS study included 763 post menopausalwomen under the age of 80 years with coronary heartdisease and intact uteri [Grady et al., 2001]. It wasdesigned to evaluate the use of estrogen in secondaryprevention of cardiac events. In a secondary analysis1525 participants who reported at least one episodeof incontinence per week at baseline were included.Participants were randomly assigned to 0.625 mg ofconjugated estrogens plus 2.5 mg of medroxy-progesterone acetate in one tablet (N=768) or placebo(N=757) and were followed for a mean of 4.1 years.Severity of incontinence was classified as improved,unchanged or worsened. The results showed thatincontinence improved in 26% of the women assignedto placebo compared to 21% assigned to hormoneswhilst 27% of the placebo worsened compared with39% of the hormone group (P=0.001).

This difference was evident by four months oftreatment, for both urgency and stress urinaryincontinence. The number of incontinent episodesper week increased an average of 0.7 in the hormonegroup and decreased by 0.1 in the placebo group (p<0.001). The authors concluded that daily oral estrogenplus progestogen therapy was associated withworsening urinary incontinence in older postmenopausal women with weekly incontinence anddid not recommend this therapy for treatment ofincontinence. However, it is possible that theprogestogen component may have had an influenceon the results of this study.

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The Women’s Health Initiative (WHI) was a multicentre double blind placebo controlled randomizedclinical trial of menopausal hormone therapy in 27347postmenopausal women age 50-79 years enrolledbetween 1992 and 1998 for whom urinary incontinencesymptoms were known in 23296 participants atbaseline and one year. The women were randomizedbased on hysterectomy status to active treatment orplacebo. Those with a uterus were given 0.625 mg perday of conjugated equine estrogen (CEE) plus 2.5mg per day of medroxyprogesterone acetate(CEE+MPA), whereas those who had undergonehysterectomy received estrogen alone (CEE). At oneyear hormone therapy was shown to increase theincidence of all types of urinary incontinence amongwomen who were continent at baseline. The risk washighest for stress urinary incontinence CEE+MPA:RR, 1.7 95% continence interval) CI (1.61-2.18); CEEalone RR 2.15 mg, 95% CI, 1.77-2.62, followed bymixed urinary incontinence CEE+MPA: RR 1.49 95%CI 1.10-2.01. On CEE alone RR was 1.79 95% CI,1.26-2.53. The combination of CEE and MPA had nosignificant effect on developing urgency urinaryincontinence RR, 1.15; 95% CI, 0.99-1.34 but CEEalone increased the risk, RR 1.32; 95% CI, 1.10-1.58.For those women experiencing urinary incontinenceat baseline frequency worsened in both active groupsCEE+MPA; RR, 1.38 95% CI 1.28-1.49; CEE alone:RR, 1.47 95% CI, 1.35-1.61. Quantity of urinaryincontinence worsened at one year in both activegroups, CEE+MPA: RR, 1.20 95% CI, 1.06-1.76; CEEalone: RR, 1.59 95% CI, 1.39-1.82. Those womenreceiving hormone therapy were more likely to reportthat urinary incontinence limited their daily activitiesCEE+MPA: RR 1.18 95% CI, 1.06-1.32. CEE alone:RR 1.29 95% CI, 1.15-1.45 at one year. Thus basedon this secondary analysis of data from a huge studyconjugated equine estrogen alone or in combinationwith medroxyprogesterone acetate was shown toincrease the risk of urinary incontinence amongstcontinent women and worsen urinary incontinenceamongst asymptomatic women after one year oftherapy.

The Nurses Health Study [Grodstein et al., 2004] wasa biennial postal questionnaire starting in 1976. In1996, 39436 post menopausal women aged 50-75years who reported no urinary leakage at the start ofthe study were followed up for four years to identifyincident cases of urinary incontinence. 5060 cases ofoccasional and 2495 cases of frequent incontinencewere identified. The risk of developing urinaryincontinence was increased amongst post menopausalwomen taking hormones compared to women who hadnever taken hormones (oral estrogen: RR1.54 95%CI 1.44, 1.65; transdermal estrogen: RR1.68, 95%CI 1.41, 2.00; oral estrogen with progestin: RR1.34,95% CI 1.24, 1.44; transdermal estrogen withprogestin: RR1.46, 95% CI 1.16, 1.84). After cessationof hormone therapy there was a decreased risk of

incontinence such that 10 years after stoppinghormones the risk was identical in women who hadand who never had taken hormone therapy.

CONCLUSIONS

Estrogen has an important physiological effect on thefemale lower urinary tract and its deficiency is anetiological factor in the pathogenesis of a number ofconditions. However the use of estrogen either aloneor in combination with progestogen has yielded poorresults. The current level 1 evidence against the useof estrogens for the treatment of urinary incontinencecomes from studies powered to assess their benefitin the prevention of cardiovascular events, andtherefore the secondary analyses have only beenbased on self reported symptoms of urinary leakagewithout any objective data. Despite this all of theselarge randomized controlled trials show a worseningof pre-existing urinary incontinence both stress andurgency, and an increased new incidence of urinaryincontinence with both estrogen and estrogen plusprogestogen. However, the majority of patients in allof these studies were taking combined equine estrogenand this may not be representative of all estrogenstaken by all routes of administration.

In a systematic review of the effects of estrogens forsymptoms suggestive of an overactive bladder theconclusion was that estrogen therapy may be effectivein alleviating OAB symptoms, and that localadministration may be the most beneficial route ofadministration [Cardozo et al., 2004].

It is quite possible that the reason for this is that thesymptoms of urinary urgency, frequency and urgencyincontinence may be a manifestation of urogenitalatrophy in older post menopausal women rather thana direct effect on the lower urinary tract [Robinsonand Cardozo, 2003]. Whilst there is good evidence thatthe symptoms and cytological changes of urogenitalatrophy may be reversed by low dose (local) vaginalestrogen therapy there is currently no evidence thatestrogens with or without progestogens should beused in the treatment of urinary incontinence.

Progesterone and progestogens are thought toincrease the risk of urinary incontinence. Lower urinarytract symptoms especially stress urinary incontinence,have been reported to increase in the progestogenicphase of the menstrual cycle [Hextall et al., 2001]. Insimilar studies progesterone has been shown toincrease β-AR activity leading to a decrease in theurethral closure pressure in female dogs [Raz et al.,1973]. However, in the WHI there appeared to be nodifference whether or not progestin was given inaddition to estrogen [Hendrix et al., 2005].

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Selective estrogen receptor modulators (SERMS)have been reported to have varying effects. Each ofthe SERMS has receptor ligand conformations that areunique and have both estrogenic and anti estrogeniceffects. In the clinical trials of levormeloxifene therewas a fourfold increase in the incidence of incontinenceleading to cessation of the clinical trial [Hendrix et al.,2001]. However raloxifene has not been shown tohave any effect at all on urinary incontinence [Waetjenet al., 2004].

There are no reported clinical trials evaluating theeffect of androgens, and in particular testosterone,on urinary incontinence in women.

The endogenous hormone vasopressin (also knownas anti-diuretic hormone) fulfils two main functions, i.e.it can contract vascular smooth muscle and canstimulate water reabsorption in the renal medulla.These functions are mediated by specific vasopressinreceptors of which two major subtypes exist, the V1and the V2 receptors of which the V2subtype isparticularly important for the anti-diuretic effects ofvasopressin. A genetic or acquired defect in makingand secreting vasopressin leads to a central diabetesinsipidus, and genetic defects in the gene encodingthe V2 receptors can cause nephrogenic diabetesinsipidus [Insel et al., 2007]. Accordingly, a (relative)lack of vasopressin is believed to be important in thepathophysiology of polyuria, specifically nocturnalpolyuria, which can lead to symptoms such as nocturia[Matthiesen et al., 1996]. While it remains largelyunknown in which fraction of patients nocturia canindeed be explained by too little vasopressin, thepresence of nocturnal polyuria in the absence ofbehavioural factors explaining it (such as excessivefluid intake) is usually considered as an indicationthat a (relative) lack of vasopressin may exist.

Based upon these considerations, vasopressinreceptor agonists have been explored for the treatmentof the symptom nocturia (both in children and in adults)and, more recently, for the treatment of OAB in general.Most studies related to the treatment of nocturia withvasopressin analogues have been performed usingdesmopressin, which shows selectivity for anti-diureticover vasopressor effects and is available informulations for oral, parenteral and nasal admi-nistration; an oral lyophilisate formulation [Vande Walleet al., 2006] has recently been approved in somecountries. Vasopressin receptor agonists withpronounced vasopressor effects such as terlipressinhave mainly been tested in other indications, e.g.,acute oesophageal variceal haemorrhage.

The use of desmopressin in children with nocturnalenuresis has been comprehensively reviewed by theCochrane Collaboration in 2002 [Glazener and Evans,

2008]. Their analysis included 47 randomizedcontrolled trials involving 3448 children, of whom 2210received desmopressin. According to this analysisdesmopressin was effective relative to placebo inreducing bed-wetting (for example at a dose of 20 µgthere was a reduction of 1.34 wet episodes/night (95%CI 1.11; 1.57), and children were more likely to becomedry with desmopressin (98%) than with placebo (81%).However, there was no difference to placebo afterdiscontinuation of treatment, indicating thatdesmopressin suppresses the symptom enuresis butdoes not cure the underlying cause. Moreover, basedupon limited data, there was no clear dose-relatedeffect, and there were too few studies to conclusivelycompare oral vs. nasal administration.

A Medline search using the terms “desmopressin”and “enuresis” did not yield additional studies whichwould change these conclusions. However, not allchildren respond sufficiently to desmopressintreatment, and some studies indicate that non-responders may benefit from other medicationsincluding tricyclic antidepressants or loop diureticswhereas muscarinic receptor antagonists may beineffective in such children [De Guchtenaere et al.,2007; Neveus and Tullus, 2008].

Other studies have explored a possible role ofdesmopressin in the treatment of nocturia in adults.The Medline search for such studies used the terms“desmopressin” and “nocturia” and was limited toclinical studies on de novo nocturia, i.e. excludedsubjects in whom childhood enuresis persisted intoadulthood. Early studies have mainly investigated theuse of desmopressin in the treatment of nocturia inthe context of multiple sclerosis. One study with singledose administration reported reductions of nocturnalpolyuria, but by design did not assess nocturia [Eckfordet al., 1995]. Three placebo-controlled double-blindstudies with small patient numbers (16-33 patientstotal per study) reported a significant reduction ofnocturia [Eckford et al., 1994; Valiquette et al., 1996;Hilton et al., 1983]. For example, in the study ofValiquette et al. [1996] performed in patients withmultiple sclerosis, the number of nocturia episodeswere reduced from 2.35 to 1.09 and the maximumhours of uninterrupted sleep form increased from 3.74to 5.77 hours. Other controlled studies of similar size,mostly performed in crossover designs, and withtreatment for up to two weeks used daytime micturitionfrequency and urgency incontinence within the first sixhours after desmopressin administration rather thannocturia as their primary endpoint and consistentlyreported efficacy of desmopressin [Kinn and Larsson,1990; Fredrikson, 1996; Hoverd and Fowler, 1998].While desmopressin treatment was generally welltolerated, at least in one study, four out of 17 patientsdiscontinued treatment due to asymptomatic orminimally symptomatic hyponatremia [Valiquette etal., 1996].

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Accordingly, desmopressin is now registered for thetreatment of nocturia in multiple sclerosis patients[Cvetkovic and Plosker, 2005]. In a small open-labelstudy desmopressin was also reported to reducenocturnal polyuria in spinal cord injury patients[Zahariou et al., 2007]. Other studies have exploredthe use of desmopressin in adults with nocturia in theapparent absence of neurological damage. Moststudies had a short double-blind period of only two tothree weeks. The recruited patient populations werebased upon different criteria including having at leasttwo nocturia episodes per night or having nocturnalpolyuria. The early studies mostly used desmopressingiven either orally [Asplund et al., 1999] or intranasally[Hilton and Stanton, 1982; Cannon et al., 1999], andtended to be very small (?25 patients). The originalintranasal formulation has meanwhile been withdrawnfrom the market in several countries due to side effectsand unpredictable absorption.

Later studies, as part of the NOCTUPUS program,were considerably larger, involving a total of 1003screened patients, and applied higher oral doses (0.1-0.4 mg) for three weeks of double-blind treatment inadults [Mattiasson et al., 2002; Lose et al., 2004; vanKerrebroeck et al., 2007]. The three short-termplacebo-controlled studies were of identical designand were designed to identify the most effective doseregimen as well as establishing criteria for selectingthose patients most likely to respond safely todesmopressin. A total of 632 patients entered thedose-titration phase with 422 patients entering thedouble-blind phase of the three NOCTUPUS trials. Theaim of the titration phase was to describe theantidiuretic effect in patients with nocturnal polyuria.It has been argued that while these studies consistentlydemonstrated efficacy over placebo in reducingnocturia episodes, they were performed in patients whowere known to be desmopressin responders basedupon initial dose-titration phases. To avoid this bias,all patients in the NOCTUPUS trials were washedout following the dose-titration and in order to berandomized it was a requirement that these patientsshould be back to baseline on their nocturnal diuresisbefore inclusion in the double-blind phase. Patientson desmopressin had a reduction in mean number ofnocturnal voids (from 2.4-2.7 to 1.6-2.0), an increasein mean duration of the first sleep period (from 181-196 to 247-272 minutes) and a decrease in meannocturnal diuresis (from 1.35 and 1.5 to 0.82 tand 0.9ml per minute [Hashim and Abrams; 2008].

The efficacy of desmopressin for the treatment ofnocturia was also confirmed in a long-term (10-12months) open-label study involving 249 patients, whichwas an extension to the above mentioned randomizedstudies in known desmopressin responders [Lose etal., 2004]. The number of nocturnal voids wasdecreased throughout the study in males to 1.3-1.6from a baseline of 3.1 and in females from 2.9 to 1.2-

1.3. After the one-month follow-up at the end of thetrial when treatment was stopped, the number ofnocturnal voids increased following cessation ofdesmopressin. The mean duration of the first sleepperiod gradually increased in males from 157 minutesat baseline to 288 minutes at 12 months and in femalesfrom 142 at baseline to 310 minutes at 12 months. Afterfollow-up the mean duration of the first sleep perioddecreased confirming that increased sleep is a realtreatment related benefit of desmopressin. There wasan improvement in QoL with more than 50% decreasein patients reporting nocturia as the most bothersomesymptom as assessed by the ICSmale and BFLUTSquestionnaires.

An open-label pilot study in a nursing home setting alsoreported beneficial effects of desmopressin [Johnsonet al., 2006]. Taken together these data demonstratethat oral desmopressin treatment at doses of 0.1-0.4mg reduces nocturia more effectively than placebo inknown desmopressin responders. Hyponatremiaappears to occur in few cases only and rarely becomessymptomatic. As the symptom of nocturia can resultfrom many causes, it has also been studied whetherdesmopressin may be beneficial in patientscharacterized not only by nocturia. In a small, non-randomized pilot study of men believed to have BPE,desmopressin was reported to improve not onlynocturia but also to reduce overall InternationalProstate Symptom Score (IPSS) [Chancellor et al.,1999].

An exploratory, placebo-controlled double-blind studyin women with daytime urinary incontinence hasreported that intranasal administration of 40 µgdesmopressin increased the number of leakage-freeepisodes after drug administration [Robinson et al.,2004]. One double-blind, placebo-controlled pilot studyin patients with OAB treated with 0.2 mg oraldesmopressin reported a reduction in daytime voidsand urgency episode along with an improvement ofquality of life, in the first eight hours of the morningafter taking desmopressin [Hashim et al., 2008]. Thesedata indicate that desmopressin may be effective instorage symptoms, not limited to nocturia (Level 2,Grade C), and desmopressin may be used as a‘designer’ drug in the treatment of OAB andincontinence during the daytime. Further studies arerequired to address this concept using the new orallypophilisate ‘Melt’ formulation either on its own or incombination with antimuscarinics and/or alpha blockersin patients with OAB and/or BPE.

Desmopressin was well tolerated in all the studiesand resulted in significant improvements compared toplacebo in reducing nocturnal voids and increasing thehours of undisturbed sleep. There was also animprovement in QoL. However, one of the mainclinically important side effects of demopressin usageis hyponatremia. Hyponatremia can lead to a varietyof adverse events ranging from mild headache,

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anorexia, nausea, and vomiting to loss ofconsciousness, seizures and death. The risk ofhyponatremia seems to increase with age, cardiacdisease, and increasing 24-hour urine volume[Rembratt et al., 2003] and has been reported in ameta-analysis to be about 7.6% [Weatherall et al.,2004].

Currently, there are no predictive factors about whomay be at increased risk of developing hyponatraemia.However, to reduce the risk of hyponatremia, it isrecommended that patients older than 79 years orwith a 24-hour urine volume more than 28 ml/kg shouldnot be given desmopressin [Rembratt et al., 2006]. Inthose over 65 years, serum sodium levels should bechecked at baseline and at three days and sevendays after commencing treatment or changing dose.It is probably good medical practice that these serumsodium measurements are also applied to those under65 years of age, as well as checking sodium levelsat three weeks post treatment or change of dose asthere is the potential for levels of sodium tomeanchange within a three week period [Callreus etal., 2005]. One study showed that hyponatraemia candevelop after six months of administration, althoughnot clinically significant [Bae et al., 2007], and thereforeserum sodium levels may be checked at six monthsfollowing administration and then six monthlythereafter. Long-term use of desmopressin does notseem to affect baseline antidiuretic hormone secretion[Bae et al., 2007]. The fluid intake will need to belimited to a minimum from one hour before the doseuntil eight hours afterwards and there needs to beperiodic blood pressure and weight measurementsto monitor for fluid overload. Desmopressin is currentlythe only medication licensed and available for thetreatment of nocturia. It is currently licensed for thetreatment of nocturia in the oral ‘Melt’ form and in theoral tablet form. For assessment, see Table 2.

Almost all randomized controlled trials ofantimuscarinics for urinary incontinence include olderadults, however only two efficacy sub-analyses ofolder adults have been reported. The first, TOLT-IR2 mg twice daily vs. placebo, revealed a significantdecrease of 0.7 episodes of incontinence per day (anapproximate 25% reduction) among 131 participantswith urgency incontinence (mean age 75, range 62-92) [Malone-Lee et al., 2001]. A second, larger studycomparing older adults (mean age 74 + 6) to youngeradults (mean age 51+ 10) taking TOLT-ER 4 mg,showed equivalent efficacy for the two age groups inreducing incontinence episodes (a mean decreaseof 12 episodes per week, an approximate 55%reduction from baseline), with both groups showing

significantly greater improvement compared to placebo(placebo response: younger 6, older 7 episodes perweek) [Zinner et al., 2002].

A number of explanations exist for why antimuscarinicagents may show reduced efficacy for urgencyincontinence in the elderly in the practice settingcompared to the research setting. Exclusion criteriafor antimuscarinic research trials generally includeconsumption of other antimuscarinic agents orcytochrome P450 3A4 inhibitors. In practice, olderadults are a heterogeneous group, often consumingmany medications that may desensitize or alter theresponse of the individual to antimuscarinics. As well,there is a higher prevalence of concomitant BPEamong older men, with storage symptoms showing avariable response to antimuscarinics. Failure toacknowledge the multifactorial nature of urinaryincontinence in the elderly often leads to sub-optimaltreatment. Urgency symptoms may be exacerbatedby consumption of caffeinated beverages, pelvic floormuscle weakness, diuretics or other functional andsystemic dysfunctions. Treatment must address allpossible etiologies, and not be limited to a solitaryintervention.

The side effect profile of antimuscarinics appears tobe the same for older and younger patients. Dry mouthis the most frequent adverse effect promptingdiscontinuation of the drug [Zinner et al., 2002]. Othermore serious side effects, such as prolongation ofthe Q-T interval with some antimuscarinics, have notbeen systematically studied in the elderly population.The M2 receptor antimuscarinics in particular have thepotential to increase resting heart rate (a predictor ofmortality in the elderly), however the clinicalsignificance of this remains uncertain [Andersson andOlshansky, 2007]. In practice, older patients mayalready be taking other antimuscarinic drugs and thusmay be habituated or intolerant to the addition ofanother medication in the same class and the resultantcumulative antimuscarinic load. A number of commonlyused medications in the elderly possess antimuscarinicproperties [Chew et al., 2008]. These include, amongothers, amytriptyline, clozapine, olanzepine,paroxetine, furosemide, hydrocodone, lansoprazole,levofloxacin, and metformin.

Of particular concern in the elderly is the possibilitythat antimuscarinic agents used to treat urgencyincontinence may induce subtle or not so subtlecognitive impairment. In experimental studies,administration of scopolamine has been shown toimpair memory and attention in older adults [Flickeret al., 1992; Sperling et al., 2002]. Older adults are alsoprone to develop hallucinations and confusion withscopolamine, and experience significantly greaterimpairments in delayed memory and psychomotorspeed compared to younger individuals.

Antimuscarinic drugs have also been associated withthe presence of mild cognitive impairment, a precursor

F. CONSIDERATIONS IN THEELDERLY

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of dementia. The Eugenia study of aging randomlyrecruited 372 adults 60 years and older fromMontpellier, France, and showed that antimuscarinicdrug users displayed significantly poorer reactiontime, attention, immediate and delayed visuospatialmemory, narrative recall, and verbal fluency than didnon drug users [Ancelin et al., 2006]. Oxybutynin inparticular, has been shown to elicit cognitiveimpairments in four case reports and one smallexperimental study [Donellan et al., 1997; Katz et al.,

1998]. The experimental study, using a double-blind,placebo-controlled cross-over design, tested aconvenience sample of 12 healthy continent olderadults, and revealed cognitive decrements on sevenof fifteen cognitive measures resulting from oxybutyninuse [Katz et al., 1998]. Impairments were observedin verbal learning, memory, reaction time, attention,concentration and psychomotor speed. In a separatesleep study, oxybutynin was found to significantly alterEEG patterns compared to placebo [Todorova et al.,2001]. There have also been several published casereports documenting the acute onset of deliriumfollowing initiation of tolterodine, in incontinent adultswith and without dementia [Womack and Heilman,2003; Salvatore et al., 2007; Edwards et al., 2002;

Williams et al., 2004; Tsao et al., 2003]. These deficitsresolved upon discontinuation or dose reduction oftolterodine. Two studies have been conducted usingdarifenacin, but only in continent volunteers [Lipton etal., 2005; Kay et al., 2006]. In the first study of 129older adults aged 65-84, no significant effects oncognition were observed (memory scanning sensitivity,speed of reaction time, and word recognition)compared with placebo [Lipton et al., 2005]. In thesecond study, darifenacin was compared to oxybutyninand placebo in a randomized multicentre double-blindparallel-group 3-week study design using 150 healthyvolunteers aged 60-83 [Kay et al., 2006]. Darifenacinproduced no impairments compared to placebo at 3-weeks, but oxybutynin caused significant memorydeterioration in delayed recall compared to the othertwo groups. Darifenacin was associated withsignificantly slower reaction times than placebo in theDivided Attention Test, but not in other tests ofinformation processing speed. Oxybutynin alsoreduced accuracy scores for immediate recall in oneof three tests. In the absence of more definitive datalinking antimuscarinics and cognition impairment,clinicians are suggested to proceed with caution inprescribing these medications and fully weigh therisk-benefit ratio in light of other therapeutic optionsthat can be equally effective for urgency and mixedincontinence in the elderly. If antimuscarinics are tobe prescribed, a short cognitive screen (such as theMontreal Cognitive Assessment) or even a fullneuropsycho-logical test battery for those patientswho are concerned or at risk, before and after initiatingtherapy might reveal whether subtle impairments havebeen induced. This is especially pertinent because

patients are often unaware of their memory deficits[Kay et al., 2006]. A proxy informant, such as thepatient’s spouse or a relative, may be able to providemore reliable information on possible cognitivechanges resulting from the drugs.

A frequently asked clinical question is whetherantimuscarinic agents used to treat incontinenceshould be contraindicated in patients with dementiaalready taking cholinesterase inhibitors, as themechanisms of these two medications are diametricallyopposed. No studies have examined the cognitiveconsequences of antimuscarinics in patients withdementia. However, a number of small studies haveshown the reverse mechanism to be true, thatcholinesterase inhibitors used to improve cognitionin Alzheimer’s disease precipitate urinary incontinence[Hashimoto et al., 2000]. A Japanese study followed94 patients with mild to moderate dementia treated withdonepezil [Hashimoto et al., 2000]. Seven patientsdeveloped urinary incontinence, although the eventwas transient in most patients. In Scotland, among 216patients with Alzheimer’s disease initiating treatmentwith a cholinesterase inhibitor, incontinence wasprecipitated in 6.6%, and those with existingincontinence worsened [Starr, 2007]. Epidemiologicstudies also show associations between cholinesteraseinhibitors and incontinence [Gill et al., 2005; Roe etal., 2002]. In a large population-based cohort studyof 44,884 adults with dementia carried out in Canada,those who were dispensed cholinesterase inhibitorswere more likely to subsequently receive anantimuscarinic drug for incontinence compared tothose not receiving cholinesterase inhibitors (hazardratio 1.55, 95% confidence interval 1.39-1.72) [Gill etal., 2005]. This finding was confirmed by a separatestudy in the U.S. documenting a two-fold risk of takingoxybutynin in dementia patients treated with donepezilcompared to those not treated with donepezil [Roe etal., 2002]. This evidence suggests the competingmechanisms of the antimuscarinics and cholinesteraseinhibitors may indeed have clinical consequences insome, but not all patients. Should an adverse effectbe suspected, then alternate therapeutic optionsshould be pursued. None of the other drug classesused to treat stress, urgency or overflow incontinencehave undergone rigorous evaluation in the elderly,however a number of general guidelines apply. Useof α-AR agonists and tricyclic antidepressants arediscouraged in the elderly due to blood pressureconsiderations. Uncontrolled systolic hypertensioncould occur with the former agents and orthostatichypotension leading to falls with the latter. There is noevidence that hormonal agents are of benefit forurgency or stress incontinence in older women,although local estrogens may be indicated to treatdysuria resulting from concomitant vaginal atrophy.Finally, removal of any offending agents that couldbe contributing to incontinence (benzodiazepines,narcotics, diuretics) should be considered.

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Abrams P, Amarenco G, Bakke A et al. Tamsulosin: efficacy andsafety in patients with neurogenic lower urinary tract dysfunctiondue to suprasacral spinal cord injury. J Urol, 2003;170(4 Pt1):1242

Abrams P, Andersson KE. Muscarinic receptor antagonists foroveractive bladder. BJU Int. 2007 Nov;100(5):987

Abrams P, Andersson K-E, Buccafusco JJ, et al. Muscarinicreceptors: their distribution and function in body systems, and theimplications for treating overactive bladder. Br J Pharmacol2006;148:565

Abrams P, Cardozo L, Chapple C et al. Comparison of the efficacy,safety, and tolerability of propiverine and oxybutynin for thetreatment of overactive bladder syndrome. Int J Urol. 2006Jun;13(6):692

Abrams P, Cardozo L, Fall M. et al. The standardisation ofterminology of lower urinary tract function: report from theStandardisation Sub-committee of the International ContinenceSociety. Neurourol Urodyn, 2002;21(2):167

Abrams P, Kelleher C, Huels J et al. Clinical relevance of health-related quality of life outcomes with darifenacin. BJU Int. 2008Jul;102(2):208

Abrams P, Swift S. Solifenacin is effective for the treatment of OABdry patients: a pooled analysis. Eur Urol. 2005 Sep;48(3):483

Agency for Healthcare Policy and Research. Urinary IncontinenceGuideline Panel. Urinary Incontinence in Adults: Clinical PracticeGuideline (AHCPR publication #92-0038). Rockville, MD, USDept. of Health and Human Services, 1992.

Akbar M, Abel R, Seyler TM et al. Repeated botulinum-A toxininjections in the treatment of myelodysplastic children and patientswith spinal cord injuries with neurogenic bladder dysfunction.BJU Int. 2007 Sep;100(3):639

Al-Badr A, Ross S, Soroka D et al. What is the available evidencefor hormone replacement therapy in women with stress urinaryincontinence? J Obstet Gynecol Can, 2003;25(7):567

Alhasso A, Glazener CMA, Pickard R et al. Adrenergic drugs forurinary incontinence in adults. Cochrane Database Syst Rev.2003:(2):CD001842

Alhasso A, Glazener CMA, Pickard R et al. Adrenergic drugs forurinary incontinence in adults (Review). Cochrane Database forSystematic Reviews 2005, Issue 3, Art. No. CD001842. DOI:10.1022/14651858. CD001842, pub 2.

Allousi S, Laval K-U, Eckert R. Trospium chloride (Spasmolyt) inpatients with motor urge syndrome (detrusor instability): a double-blind, randomised, nulticentre, placebo-controlled study. J Clin Res1998;1:439

Altaweel W, Jednack R, Bilodeau C et al. Repeated intradetrusorbotulinum toxin type A in children with neurogenic bladder dueto myelomeningocele. J Urol. 2006 Mar;175(3 Pt 1):1102

Amarenco G, Marquis P, McCarthy C et al. Qualité de vie desfemmes souffrant d´mpériosité mictionelle avec ou sans fuites:étude prospective aprés traitement par oxybutinine (1701 cas).Presse Medicale, 1998;27:5

Ancelin ML, Artero S, Portet F et al. Non-degenerative mildcognitive impairment in elderly people and use of anticholinergicdrugs: longitudinal cohort study. BMJ 2006;332:455

Anders RJ, Wang E, Radhakrishnan J et al. Overflow urinaryincontinence due to carbamazepine. J Urol 1985; 134: 758

Anderson RU, Mobley D, Blank B. et al. Once-daily controlledversus immediate-release oxybutynin chloride for urge urinaryincontinence. OROS Oxybutynin Study Group. J Urol1999;161:1809

Andersson K-E: Current concepts in the treatment of disordersof micturition. Drugs 1988;35:477

Andersson, K.-E. Pharmacology of lower urinary tract smoothmuscles and penile erectile tissues. Pharmacol Rev, 45:253,1993.

Andersson K-E. Pathways for relaxation of detrusor smoothmuscle. In: Advances in Bladder Research, ed by Baskin LS andHayward SW, Kluwer Academic/Plenum Publishers, New York1999, p 241

Andersson KE. Bladder activation: afferent mechanisms. Urology.2002 May;59(5 Suppl 1):43

Andersson K-E. Potential benefits of muscarinic M3 receptorselectivity. Eur Urol Suppl, 2002;1(4):23

Andersson K-E. Alpha-adrenoceptors and benign prostatichyperplasia: basic principles for treatment with alpha-adrenoceptorantagonists. World J Urol 2002;19(6):390

Andersson KE. Antimuscarinics for treatment of overactive bladder.Lancet Neurol. 2004 Jan;3(1):46 .

Andersson KE. LUTS treatment: future treatment options.Neurourol Urodyn. 2007 Oct;26(6 Suppl):934-47.

Andersson K-E. How many drugs for LUTS due to BPH are toomany? J Urol. 2008 Sep;180(3):811

Andersson, K.-E., Appell, R., Awad, S. et al. Pharmacologicaltreatment of urinary incontinence, in Abrams P, Khoury S, WeinA (Eds), Incontinence, 2nd International Consultation onIncontinence. Plymouth, Plymbridge Distributors Ltd, UK,Plymouth, p 479, 2002

Andersson KE, Appell R, Cardozo LD et al. The pharmacologicaltreatment of urinary incontinence. BJU Int 1999 Dec;84(9):923

Andersson K-E, Appell R, Cardozo L et al. Pharmacologicaltreatment of urinary incontinence, in Abrams P, Khoury S, WeinA (Eds), Incontinence, 3rd International Consultation onIncontinence. Plymouth, Plymbridge Distributors Ltd, UK,Plymouth, p 811, 2005

Andersson K-E, Chapple CR. Oxybutynin and the overactivebladder. World J Urol 2001;19(5):319

Andersson K-E, Fullhase C, Soler R. Urothelial effects of oralantimuscarinic agents. Current Urology Reports 2008bNov;9(6):459

Andersson KE, Pehrson R. CNS involvement in overactive bladder:pathophysiology and opportunities for pharmacologicalintervention. Drugs. 2003;63(23):2595

Andersson KE, Olshansky B. Treating patients with overactivebladder syndrome with antimuscarinics: heart rate considerations.BJU International 2007;100:1007

Andersson K-E, Persson K. The L-arginine/nitric oxide pathwayand non-adrenergic, non-cholinergic relaxation of the lower urinarytract. 1993;Gen Pharmacol 24:833

Andersson K-E, Uckert S, Stief C et al. Phosphodiesterases(PDEs) and PDE inhibitors for treatment of LUTS. NeurourolUrodyn 1997 Oct;26(6Suppl):928

Andersson K-E, Wein AJ. Pharmacology of the Lower Urinary Tract- Basis for Current and Future Treatments of Urinary Incontinence.Pharmacol Rev 2004 Dec; 56(4):581

Andersson MC, Tobin G, Giglio D. Cholinergic nitric oxide releasefrom the urinary bladder mucosa in cyclophosphamide-inducedcystitis of the anaesthetized rat. Br J Pharmacol 2008a;153:1438.

Aoki KR. Review of a proposed mechanism for the antinociceptiveaction of botulinum toxin type A. Neurotoxicology. 2005Oct;26(5):785

Apostolidis A, Gonzales GE, Fowler CJ, Effect of intravesicalResiniferatoxin (RTX) on lower urinary tract symptoms, urodynamicparameters, and quality of life of patients with urodynamicincreased bladder sensation. Eur Urol. 2006 Dec;50(6):1299

Apostolidis A, Popat R, Yiangou Y et al. Decreased sensoryreceptors P2X3 and TRPV1 in suburothelial nerve fibers followingintradetrusor injections of botulinum toxin for human detrusoroveractivity. J Urol. 2005 Sep;174(3):977

REFERENCES

684

Appell RA, Chancellor MB, Zobrist RH et al. Pharmacokinetics,metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects. MayoClin Proc, 2003;78(6):696, 2003.

Appell RA, Sand P, Dmochowski R et al. Overactive bladder:judging effective control and treatment study group. Prospectiverandomized controlled trial of extended-release oxybutynin chlorideand tolterodine tartrate in the treatment of overactive bladder:results of the OBJECT Study. Mayo Clin Proc, 2001;76(4):358

Arnold EP. Tamsulosin in men with confirmed bladder outletobstruction: a clinical and urodynamic analysis from a singlecentre in New Zealand. BJU Int 2001;87(1):24

Aschkenazi S, Botros S, Miller J et al. Overactive bladdersymptoms are not related to detrusor overactivity. NeurourolUrodyn, 2007;26(5), abstract 35

Asplund R, Sundberg B, Bengtsson P. Oral desmopressin fornocturnal polyuria in elderly subjects: a double-blind, placebo-controlled randomized exploratory study. BJU Int 1999;83:591

Athanasopoulos A, Gyftopoulos K, Giannitsas K et al. G.Combination treatment with an alpha-blocker plus ananticholinergic for bladder outlet obstruction: a prospective,randomized, controlled study. J Urol 2003; 169:2253

Athwal BS, Berkley KJ, Hussain I. et al. Brain responses tochanges in bladder volume and urge to void in healthy men.Brain, 2001;124(Pt 2):369

Badawi JK, Seja T, Uecelehan H et al. Relaxation of humandetrusor muscle by selective beta-2 and beta-3 agonists andendogenous catecholamines. Urology. 2007 Apr;69(4):785

Bae JH, Oh MM, Shim KS et al. The effects of long-termadministration of oral desmopressin on the baseline secretion ofantidiuretic hormone and serum sodium concentration for thetreatment of nocturia: a circadian study. J. Urol 2007;178(1):200

Baigrie RJ, Kelleher JP, Fawcett DP et al. Oxybutynin: is it safe?Br J Urol, 1988;62:319 Jonville AP, Dutertre JP, Autret E et al.Effets indésirables du chlorure d´oxybutynine (Ditropan®).Therapie 1992;47:389

Baldessarini KJ. Drugs in the treatment of psychiatric disorders.In: Gilman et al. (Eds.) The pharmacological basis of therapeutics,7th ed., McMillan Publishing Co., p387, 1985

Baldo A, Berger TH, Kofler M et al.: The influence of intrathecalbaclofen on detrusor function. A urodynamic study. NeuroUrolUrodyn, 2000, 19, 444 (abstract 53).

Bayliss M, Wu C, Newgreen D et al. A quantitative study ofatropine-resistant contractile responses in human detrusor smoothmuscle, from stable, unstable and obstructed bladders. J Urol1999;162:1833

Barendrecht MM, Oelke M, Laguna MP et al. Is the use ofparasympathomimetics for treating an underactive urinary bladderevidence-based? BJU Int 2007;99:749

Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R et al. Inhibitoryeffects of trospium chloride on cytochrome P450 enzymes inhuman liver microsomes. Pharmacol Toxicol, 1999;(6):299

Beermann B, Hellstrom K, Rosen A. On the metabolism ofpropantheline in man. Clin Pharmacol Ther, 1972; 13(2):212

Bent AE, Gousse AE, Hendrix SL et al. Duloxetine comparedwith placebo for the treatment of women with mixed urinaryincontinence. Neurourol Urodyn. 2008;27(3):212

Bent S, Tiedt TN, Odden MC, et al. The relative safety of ephedracompared with other herbal products. Ann Intern Med.2003;138(6):468

Bharucha AE, Seide B, Guan Z et al. Effect of tolterodine ongastrointestinal transit and bowel habits in healthy subjects.Neurogastroenterol Motil. 2008 Jun;20(6):643

Biers SM, Reynard JM, Brading AF. The effects of a new selectivebeta3-adrenoceptor agonist (GW427353) on spontaneous activityand detrusor relaxation in human bladder. BJU Int. 2006Dec;98(6):1310

Bigger JT, Giardina EG, Perel JM et al. Cardiac antiarrhythmiceffect of imipramine hydrochloride. N Engl J Med 1977;296:206

Birder LA, de Groat WC. Mechanisms of disease: involvementof the urothelium in bladder dysfunction. Nat Clin Pract Urol.2007 Jan;4(1):46-54.

Blaivas JG, Labib KB, Michalik J et al. Cystometric response topropantheline in detrusor hyperreflexia: therapeutic implications.J Urol, 1980;124:259

Blue DR, Daniels DV, Gever JR et al. Pharmacologicalcharacteristics of Ro 115-1240, a selective? 1A-1L- adrenoceptorpartial agonist: a potential therapy for stress urinary incontinence.BJU Int 2004;93(1):162

Bosch RJLH, Griffiths DJ, Blom JHM et al. Treatment of benignprostatic hyperplasia by androgen deprivation: effects on prostatesize and urodynamic parameters. J Urol 1989;141:68

Boy S, Seif C, Braun PM et al. Retrospective Analysis of treatmentoutcomes and medical care of patients with neurogenic detrusoroveractivity (NDO) receiving BOTOX therapy. European UrologySupplements, 2008;7 (3):212

Brady CM, Apostolidis AN, Harper M et al. Parallel changes inbladder suburothelial vanilloid receptor TRPV1 and pan-neuronalmarker PGP9.5 immunoreactivity in patients with neurogenicdetrusor overactivity after intravesical resiniferatoxin treatment.BJU Int. 2004 Apr;93(6):770

Braverman AS, Doumanian LR, Ruggieri MR, Sr. M2 and M3muscarinic receptor activation of urinary bladder contractile signaltransduction. II. Denervated rat bladder. J Pharmacol Exp Ther2006;316:875

Braverman AS, Karlovsky M, Pontari MA et al. Aging andhypertrophy change the muscarinic receptor subtype mediatingbladder contraction from M3 towards M2. J Urol 2002;167 Suppl.:Abstract #170.

Braverman AS, Kohn IJ, Luthin GR et al. Prejunctional M1facilitatory and M2 inhibitory muscarinic receptors mediate ratbladder contractility. Am J Physiol 1998;274: R517

Braverman AS, Luthin GR, Ruggieri MR. M2 muscarinic receptorcontributes to contraction of the denervated rat urinary bladder.Am J Physiol 1998;275:R1654

Braverman AS, Ruggieri MR, Sr. Hypertrophy changes themuscarinic receptor subtype mediating bladder contraction fromM3 toward M2. Am J Physiol 2003;285:R701

Bridgewater M, Brading AF. Evidence for a non-nitrergicinhibitory innervation in the pig urethra. Neurourol Urodyn1993;12:357

Briggs KS, Castleden CM, Asher MJ. The effect of flavoxate onuninhibited detrusor contractions and urinary incontinence in theelderly. J Urol 1980;123:665

Brubaker L, FitzGerald MP. Nocturnal polyuria and nocturia reliefin patients treated with solifenacin for overactive bladdersymptoms. Int Urogynecol J Pelvic Floor Dysfunct. 2007Jul;18(7):737

Brubaker L, Richter HE, Visco A et al. Pelvic Floor DisordersNetwork, Refractory idiopathic urge urinary incontinence andbotulinum A injection. J Urol. 2008 Jul;180(1):217

Brynne N, Dalen P, Alvan G et al. Influence of CYP2D6polymorphism on the pharmacokinetics and pharmacodynamicsof tolterodine. Clin Pharmacol Ther 1998;63:529

Brynne N, Stahl MMS, Hallén B et al. J. Pharmacokinetics andpharmacodynamics of tolterodine in man: a new drug for thetreatment of urinary bladder overactivity. Int J Clin PharmacolTher 1997;35:287

Bschleipfer T, Schukowski K, Weidner W, et al. Expression anddistribution of cholinergic receptors in the human urothelium. LifeSci 2007;80:2303

Bump RC, Voss S, Beardsworth A et al. Long-term efficacy of

685

duloxetine in women with stress urinary incontinence. Br J UrolInt 2008;102:214

Bushman W, Steers WD, Meythaler JM, Voiding dysfunction inpatients with spastic paraplegia: urodynamic evaluation andresponse to continuous intrathecal baclofen. Neurourol Urodyn.1993;12(2):163

Caine M, Gin S, Pietra C et al. Antispasmodic effects of flavoxate,MFCA, and REC 15/2053 on smooth muscle of human prostateand urinary bladder. Urology 1991;37(4):390

Callreus T, Ekman E, Andersen M. Hyponatremia in elderlypatients treated with desmopressin for nocturia: a review of a caseseries. Eur. J. Clin. Pharmacol 2005;61(4):281

Cannon A, Carter PG, McConnell AA et al. Desmopressin in thetreatment of nocturnal polyuria in the male. BJU Int 1999; 84:20

Carbone A, Palleschi G, Conte A et al. Gabapentin treatment ofneurogenic overactive bladder. Clin Neuropharmacol. 2006 Jul-Aug;29(4):206

Cardozo L, Castro-Diaz D, Gittelman M et al. Reductions inoveractive bladder-related incontinence from pooled analysis ofphase III trials evaluating treatment with solifenacin. Int UrogynecolJ Pelvic Floor Dysfunct. 2006 Sep;17(5):512

Cardozo L, Chapple CR, Toozs-Hobson P et al. Efficacy oftrospium chloride in patients with detrusor instability: a placebo-controlled, randomized, double-blind, multicentre clinical trial.BJU Int 2000;85(6):659

Cardozo L, Dixon A. Increased warning time with darifenacin: anew concept in the management of urinary urgency. J Urol. 2005Apr;173(4):1214

Cardozo L, Drutz HP, Baygani SK et al. Pharmacological treatmentof women awaiting surgery for stress urinary incontinence. ObstetGynecol 2004;104:511 Kinchen KS,

Cardozo L, Lisec M, Millard R et al. Randomized, double-blindplacebo controlled trial of the once daily antimuscarinic agentsolifenacin succinate in patients with overactive bladder. J Urol.2004 Nov;172(5 Pt 1):1919

Cardozo L, Lose G, McClish D et al. A systematic review of theeffects of estrogens for symptoms suggestive of overactivebladder. Acta Obstetr Gynaecol Scand 2004;83:892

Cardozo L, Rekers H, Tapp A et al. Oestriol in the treatment ofpostmenopausal urgency: a multicentre study. Maturitas1993;18:47

Cardozo LD, Stanton SL. A comparison between bromocriptineand indomethacin in the treatment of detrusor instability. J Urol1980;123:39

Cardozo LD, Stanton SL, Robinson H et al. Evaluation onflurbiprofen in detrusor instability. Br Med J 1980;280:281

Cartwright R, Cardozo L. Transdermal oxybutynin: sticking tothe facts. Eur Urol. 2007 Apr;51(4):907

Castleden CM, Morgan B. The effect of ß-adrenoceptor agonistson urinary incontinence in the elderly. Br J Clin Pharmacol1980;10:619

Castro-Diaz D, Palma PCR, Bouchard C et al. Effect of doseescalation on the tolerability and efficacy of duloxetine in thetreatment of women with stress urinary incontinence. IntUrogynecol J 2007; 18:919

Catterall WA, Striessnig J, Snutch TP et al. International Unionvof Pharmacology. XL. Compendium of voltage-gated ion channels:calcium channels. Pharmacol Rev 2003;55:579

Caulfield MP, Birdsall NJM. International Union of Pharmacology.XVII. Classification of muscarinic acetylcholine receptors.Pharmacol Rev 1998;50:27

Cazzulani P, Pietra C, Abbiati GA et al. Pharmacological activitiesof the main metabolite of flavoxate 3-methylflavone-8-carboxylicacid. Arzneimittelforschung, 1988;38(3):379

Chai TC, Gray ML, Steers WD, The incidence of a positive ice

water test in bladder outlet obstructed patients: evidence forbladder neural plasticity. J Urol. 1998 Jul;160(1):34

Chancellor MB, Appell RA, Sathyan G et al. A comparison of theeffects on saliva output of oxybutynin chloride and tolterodinetartrate. Clin Ther 2001;23(5):753

Chancellor MB, Atan A, Rivas DA et al. Beneficial effect ofintranasal desmopressin for men with benign prostatic hyperplasiaand nocturia: preliminary results. Tech Urol 1999;5:191

Chancellor MB, Fowler CJ, Apostolidis A et al. Drug Insight:biological effects of botulinum toxin A in the lower urinary tract.Nat Clin Pract Urol. 2008 Jun;5(6):319

Chancellor MB, Kianifard F, Beamer E et al. A comparison of theefficacy of darifenacin alone vs. darifenacin plus a BehaviouralModification Programme upon the symptoms of overactive bladder.Int J Clin Pract. 2008 Apr;62(4):606

Chapple CR, Arano P, Bosch JL et al. Solifenacin appears effectiveand well tolerated in patients with symptomatic idiopathic detrusoroveractivity in a placebo- and tolterodine-controlled phase 2dosefinding study. 2004a;BJU Int, 93(1):71

Chapple CR, Cardozo L, Steers WD et al. Solifenacin significantlyimproves all symptoms of overactive bladder syndrome. Int JClin Pract. 2006 Aug;60(8):959

Chapple C, DuBeau C, Ebinger U et al. Long-term darifenacintreatment for overactive bladder in patients aged 65 years andolder: analysis of results from a 2-year, open-label extensionstudy. Curr Med Res Opin. 2007 Nov;23(11):2697

Chapple CR, Fianu-Jonsson A, Indig M et al. STAR study group.Treatment outcomes in the STAR study: a subanalysis ofsolifenacin 5 mg and tolterodine ER 4 mg. Eur Urol. 2007Oct;52(4):1195

Chapple C, Khullar V, Gabriel Z et al. The effects of antimuscarinictreatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005;48:5

Chapple CR, Khullar V, Gabriel Z et al. The effects ofantimuscarinic treatments in overactive bladder: an update of asystematic review and meta-analysis. Eur Urol. 2008Sep;54(3):543

Chapple CR, Martinez-Garcia R, Selvaggi L et al. A comparisonof the efficacy and tolerability of solifenacin succinate and extendedrelease tolterodine at treating overactive bladder syndrome:results of the STAR trial. Eur Urol. 2005 Sep;48(3):464

Chapple CR, Parkhouse H, Gardener C et al. Double-blind,placebo-controlled, cross-over study of flavoxate in the treatmentof idiopathic detrusor instability. Br J Urol 1990;66:491

Chapple CR, Patroneva A, Raines SR. Effect of an ATP-sensitivepotassium channel opener in subjects with overactive bladder:a randomized, double-blind, placebo-controlled study(ZD0947IL/0004). Eur Urol 2006; 49: 879

Chapple CR, Rechberger T, Al-Shukri, S et al. YM-905 StudyGroup. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacinin patients with symptomatic overactive bladder. BJU Int2004b;93(3):303

Chapple C, Steers W, Norton P et al. A pooled analysis of threephase III studies to investigate the efficacy, tolerability and safetyof darifenacin, a muscarinic M3 selective receptor antagonist, inthe treatment of overactive bladder. BJU Int. 2005 May;95(7):993

Chapple CR, Van Kerrebroeck PE, Jünemann KP et al.Comparison of fesoterodine and tolterodine in patients withoveractive bladder. BJU Int. 2008 Jul 21. [Epub ahead of print]

Chapple C, Van Kerrebroeck P, Tubaro A et al. Clinical efficacy,safety, and tolerability of once-daily fesoterodine in subjects withoveractive bladder. Eur Urol. 2007 Oct;52(4):1204

Chapple CR, Yamaguchi O, Ridder A et al. Clinical proof ofconcept study (Blossom) shows novel b3 adrenoceptor agonistYM178 is effective and well tolerated in the treatment of symptoms

686

of overactive bladder. Eur Urol Suppl 2008;7(3):239 (abstract674)

Charrua A, Cruz CD, Narayanan S et al. GRC 6211 a new specificoral TRPV1 antagonist reduces bladder overactivity and noxiousbladder input in cystitis animal models. J Urol 2008, in press.

Chess-Williams R. Muscarinic receptors of the urinary bladder:detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol2002;22:133

Chess-Williams R, Chapple CR, Yamanishi T et al. The minorpopulation of M3-receptors mediate contraction of human detrusormuscle in vitro. J Auton Pharmacol 2001;21:243

Chew ML, Mulsant BH, Pollock BG et al. Anticholinergic activityof 107 medications commonly used by older adults. J Am GeriatrSoc. 2008 May 26. Epub ahead of publication.

Choo MS, Doo CK, Lee KS. Satisfaction with tolterodine: assessingsymptom-specific patient-reported goal achievement in thetreatment of overactive bladder in female patients (STARGATEstudy). Int J Clin Pract. 2008 Feb;62(2):191

Christ GJ, Andersson KE. Rho-kinase and effects of Rho-kinaseinhibition on the lower urinary tract. Neurourol Urodyn. 2007Oct;26(6 Suppl):948

Chuang YC, Thomas CA, Tyagi S, et al.: Human urine withsolifenacin intake but not tolterodine or darifenacin intake blocksdetrusor overactivity. Int Urogynecol J Pelvic Floor Dysfunct 2008Oct;19(10):1353

Chutka DS, Takahashi PY. Urinary incontinence in the elderly. Drugtreatment options. Drugs 1998; 56: 587

Citeri M, Spinelli M, Zanollo L et al. Botulinum tonix into thetrigone in neurogenic overactive bladder non responder to detrusorinjection. Eur Urol Suppl, 2008:7 (3):213

Clemett D, Jarvis B. Tolterodine: a review of its use in the treatmentof overactive bladder. Drugs Aging, 2001;18(4):277

Cockayne DA, Hamilton SG, Zhu QM et al. Urinary bladderhyporeflexia and reduced pain-related behaviour in P2X3-deficientmice. Nature, 2000;407(6807):1011

Collas D, Malone-Lee JG. The pharmacokinetic properties ofrectal oxybutynin - a possible alternative to intravesicaladministration. Neurourol Urodyn 1997;16:346

Colli E, Digesu GA, Olivieri L. Overactive bladder treatments inearly phase clinical trials. Expert Opin Investig Drugs. 2007Jul;16(7):999-1007.

Colli E, Rigatti P, Montorsi F et al. BXL628, a novel vitamin D3analog arrests prostate growth in patients with benign prostatichyperplasia: a randomized clinical trial. Eur Urol. 2006 Jan;49(1):82

Compérat E, Reitz A, Delcourt A et al. Histologic features in theurinary bladder wall affected from neurogenic overactivity--acomparison of inflammation, oedema and fibrosis with and withoutinjection of botulinum toxin type A. Eur Urol. 2006 Nov;50(5):1058

Connolly MJ, Astridge PS, White EG, Morley CA, Cowan JC.Torsades de pointes ventricular tachycardia and terodiline. Lancet.1991 Aug 10;338(8763):344

Copas PM, Bukovsky A, Asubyr B et al. Estrogen, progesteroneand androgen receptor expression in levator ani muscle andfascia. J Womens Health Gend Based Med 2001;10(8):785

Corcos J, Al-Taweel W, Pippi Salle J et al. The Treatment of detrusorhyperreflexia using botulinum A toxin in myelomeningocele patientsunresponsive to anticholinergic International Continence SocietyAnnual Meeting. 2002: Abstract 39

Corcos J, Casey R, Patrick A et al. A double-blind randomizeddose-response study comparing daily doses of 5, 10 and 15 mgcontrolled-release oxybutynin: balancing efficacy with severityof dry mouth. BJU Int. 2006 Mar;97(3):520

Covenas R, Martin F, Belda M et al. Mapping of neurokinin-likeimmunoreactivity in the human brainstem. BMC Neurosci Febr4(1):3

Coyne KS, Elinoff V, Gordon DA et al. Relationships betweenimprovements in symptoms and patient assessments of bladdercondition, symptom bother and health-related quality of life inpatients with overactive bladder treated with tolterodine. Int JClin Pract. 2008 Jun;62(6):925

Crescioli C, Ferruzzi P, Caporali A et al. Inhibition of spontaneousand androgen-induced prostate growth by a nonhypercalcemiccalcitriol analog. Endocrinology. 2003 Jul;144(7):3046

Crescioli C, Ferruzzi P, Caporali A et al. Inhibition of prostate cellgrowth by BXL-628, a calcitriol analogue selected for a phase IIclinical trial in patients with benign prostate hyperplasia. Eur JEndocrinol. 2004 Apr;150(4):591

Cruz F, Charrua A, Cruz C et al. GRC 1: A new oral TRPV1antagonist, decreases the frequency of bladder reflex contractionsand noxious input in rats with acute or chronic cystitis. Eur Urol2008;Suppl 7(3):181.

Cruz F, Dinis P Resiniferatoxin and botulinum toxin type A fortreatment of lower urinary tract symptoms. Neurourol Urodyn. 2007Oct;26(6 Suppl):920

Cruz F, Guimaräes M, Silva C et al. Suppression of bladderhyperreflexia by intravesical resiniferatoxin. Lancet. 1997 Aug30; 350 (9078):640

Cruz F, Silva C. Botulinum toxin in the management of lowerurinary tract dysfunction: contemporary update. Curr Opin Urol.2004 Nov;14(6):329

Cvetkovic RS, Plosker GL. Desmopressin in adults with nocturia.Drugs 2005;65:99

D'Agostino G, Barbieri A, Chiossa E et al. M4 muscarinicautoreceptor-mediated inhibition of [3H]acetylcholine release inthe rat isolated urinary bladder. J Pharmacol Exp Ther1997;283:750

Dahm TL, Ostri P, Kristensen JK et al. Flavoxate treatment ofmicturition disorders accompanying benign prostatic hypertrophy:a double-blind placebo-controlled multicenter investigation. UrolInt 1955;55:205

Das A, Chancellor MB, Watanabe T et al. Intravesical capsaicinin neurologic impaired patients with detrusor hyperreflexia. JSpinal Cord Med. 1996 Jul;19(3):190

Davila GW, Daugherty CA, Sanders SW. A short-term, multicenter,randomized double-blind dose titration study of the efficacy andanticholinergic side effects of transdermal compared to immediaterelease oral oxybutynin treatment of patients with urge urinaryincontinence. J Urol 2001;166(1):140

Deaney C, Glickman S, Gluck T et al. Intravesical atropinesuppression of detrusor hyperreflexia in multiple sclerosis. JNeurol Neurosurg Psychiatry 1998;65:957

Debruyne F, Gres AA, Arustamov DL. Placebo-controlled dose-ranging phase 2 study of subcutaneously administered LHRHantagonist cetrorelix in patients with symptomatic benign prostatichyperplasia. Eur Urol. 2008 Jul;54(1):170

de Groat WC, A neurologic basis for the overactive bladder.Urology. 1997 Dec; 50 (6A Suppl):36-52; discussion 53

de Groat, WC, Booth AM, Yoshimura N. Neurophysiology ofmicturition and its modification in animal models of human disease.In: The Autonomic Nervous System. Vol. 6, Chapter 8, NervousControl of the Urogenital System, ed. by C.A. Maggi. HarwoodAcademic Publishers, London, U.K., p. 227, 1993.

de Groat WC, Downie JW, Levin RM et al. Basic neurophysiologyand neuropharmacology, in Abrams P, Khoury S, Wein A (Eds),Incontinence, 1st International Consultation on Incontinence.Plymouth, United Kingdom, Plymbridge Distributors Ltd, p. 105,1999.

de Groat, W.C., and Yoshimura N. Pharmacology of the lowerurinary tract. Annu Rev Pharmacol Toxicol, 41:691, 2001

De Guchtenaere A, Vande Walle C, Van Sintjan P et al.Desmopressin resistant nocturnal polyuria may benefit from

687

furosemide therapy administered in the morning. J Urol2007;178:2635

De Laet K, De Wachter S, Wyndaele JJ. Systemic oxybutynindecreases afferent activity of the pelvic nerve of the rat: newinsights into the working mechanism of antimuscarinics. NeurourolUrodyn. 2006;25(2):156

DeLancey JOL. The pathophysiology of stress urinary incontinencein women and its implications for surgical treatment. World JUrol 1997;15:268

Del Popolo G. Botulinum toxin a era: little steps towards a betterunderstanding. Eur Urol. 2008 Jul;54(1):25

Del Popolo G, Filocamo MT, Li Marzi V et al. Neurogenic detrusoroveractivity treated with english botulinum toxin a: 8-yearexperience of one single centre. Eur Urol. 2008 May;53(5):1013

de Paiva A, Meunier FA, Molgó J et al. Functional repair of motorendplates after botulinum neurotoxin type A poisoning: biphasicswitch of synaptic activity between nerve sprouts and their parentterminals. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3200

De Ridder D, Chandiramani V, Dasgupta P et al. Intravesicalcapsaicin as a treatment for refractory detrusor hyperreflexia: adual center study with long-term followup. J Urol. 1997Dec;158(6):2087

de Sèze M, Gallien P, Denys P et al. Intravesical glucidic capsaicinversus glucidic solvent in neurogenic detrusor overactivity: adouble blind controlled randomized study. Neurourol Urodyn.2006;25(7):752

de Sèze M, Wiart L, Joseph PA et al. Capsaicin and neurogenicdetrusor hyperreflexia: a double-blind placebo-controlled studyin 20 patients with spinal cord lesions. Neurourol Urodyn.1998;17(5):513

Diefenbach K, Jaeger K, Wollny A et al. Effect of tolterodine onsleep structure modulated by CYP2D6 genotype. Sleep Med2008Jul;9(5)579

Digesu GA, Khullar V, Cardozo L, Salvatore S. Overactive bladdersymptoms: do we need urodynamics? Neurourol Urodyn.2003;22(2):105

Dinis P, Silva J, Ribeiro MJ et al. Bladder C-fiber desensitizationinduces a long-lasting improvement of BPH-associated storageLUTS: a pilot study. Eur Urol. 2004Jul;46(1):88

Diokno AC, Appell RA, Sand PK et al. Prospective, randomized,double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactivebladder: results of the OPERA trial. Mayo Clin Proc 2003;78(6):687

Dmochowski R, Abrams P, Marschall-Kehrel D et al. Efficacy andtolerability of tolterodine extended release in male and femalepatients with overactive bladder. Eur Urol. 2007 Apr;51(4):1054

Dmochowski RR, Davila GW, Zinner NR et al. Efficacy and safetyof transdermal oxybutynin in patients with urge and mixed urinaryincontinence. J Urol 2002;168(2):580

Dmochowski R, Kreder K, MacDiarmid S et al. The clinical efficacyof tolterodine extended-release is maintained for 24 h in patientswith overactive bladder. BJU Int. 2007 Jul;100(1):107

Dmochowski RR, Miklos JR, Norton PA et al. Duloxetine vs.placebo in the treatment of North American women with stressurinary incontinence. J Urol 2003;170:1259

Dmochowski RR, Nitti V, Staskin D et al. Transdermal oxybutyninin the treatment of adults with overactive bladder: combinedresults of two randomized clinical trials. World J Urol. 2005Sep;23(4):263

Dmochowski R, Sand PK. Botulinum toxin A in the overactivebladder: current status and future directions. BJU Int. 2007Feb;99(2):247

Dmochowski RR, Sand PK, Zinner NR et al. Comparative efficacyand safety of transdermal oxybutynin and oral tolterodine versusplacebo in previously treated patients with urge and mixed urinaryincontinence. Urology, 2003;62(2):237

Dmochowski RR, Sand PK, Zinner NR et al. Trospium 60 mg oncedaily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study. Urology 2008 Mar;71(3):449

Dong M, Yeh F, Tepp WH et al. SV2 is the protein receptor forbotulinum neurotoxin A. Science. 2006 Apr 28;312(5773):592

Donker P, Van der Sluis C. Action of beta adrenergic blockingagents on the urethral pressure profile. Urol Int 1976;31:6

Donnellan CA, Fook L, McDonald P et al. Oxybutynin and cognitivedysfunction. BMJ 1997;315:1363

Doroshyenko O, Jetter A, Odenthal KP et al. Clinicalpharmacokinetics of trospium chloride. Clin Pharmacokinet.2005;44(7):701

Dorschner W, Stolzenburg JU, Griebenow R et al. Efficacy andcardiac safety of propiverine in elderly patients - a double-blind,placebo-controlled clinical study. Eur Urol 2000;37:702

Douchamps J, Derenne F, Stockis A et al. The pharmacokineticsof oxybutynin in man. Eur J Clin Pharmacol, 1988;35:515

Downie JW, Karmazyn M. Mechanical trauma to bladderepithelium liberates prostanoids which modulate neuro-transmission in rabbit detrusor muscle. J Pharmacol Exp Ther1984;230: 445

Dwyer P, Kelleher C, Young J et al. Long-term benefits ofdarifenacin treatment for patient quality of life: results from a 2-year extension study. Neurourol Urodyn. 2008;27(6):540

Dwyer PL, Teele JS. Prazosin: a neglected cause of genuinestress incontinence. Obstet Gynecol 1992;79:117

Dykstra D, Enriquez A, Valley M. Treatment of overactive bladderwith botulinum toxin type B: a pilot study. Int Urogynecol J PelvicFloor Dysfunct. 2003 Dec;14(6):424

Eckford SD, Carter PG, Jackson SR et al. An open, in-patientincremental safety and efficacy study of desmopressin in womenwith multiple sclerosis and nocturia. Br J Urol 1995;76:459

Eckford SD, Swami KS, Jackson SR et al. Desmopressin in thetreatment of nocturia and enuresis in patients with multiplesclerosis. Br J Urol 1994;74:733

Edwards KR, O’Connor JT. Risk of delirium with concomitantuse of tolterodine and acetylcholinesterase inhibitors. J Am GeriatrSoc 2002;50:1165

Ehlert FJ, Ahn S, Pak KJ, et al. Neuronally release acetylcholineacts on the M2 muscarinic receptor to oppose the relaxant effectof isoproterenol on cholinergic contractions in mouse urinarybladder. J Pharmacol Exp Ther 2007; 322:631

Ehren I, Volz D, Farrelly E et al. Efficacy and impact of botulinumtoxin A on quality of life in patients with neurogenic detrusoroveractivity: a randomised, placebo-controlled, double-blind study.Scand J Urol Nephrol. 2007;41(4):335

Eichel R, Lang C, Alloussi SH et al. Botulinum Toxin A(DYSPORT®), A safe modern treatment regime in the therapy ofdrug refractorical detrusor overactivity, 5 years of clinicalexperience. Eur Urol Suppl, 2008;7(3):213.Ekström B, Andersson K-E, Mattiasson A. Urodynamic effects ofintravesical instillation of atropine and phentolamine in patientswith detrusor hyperactivity. J Urol 1992;149:155 Elinoff V, Bavendam T, Glasser DB et al. Symptom-specificefficacy of tolterodine extended release in patients with overactivebladder: the IMPACT trial. Int J Clin Pract. 2006 Jun;60(6):745 Endo RM, Girao MJ, Sartori MG et al. Effect of estrogen-progestogen hormonal replacement therapy on periurethral andbladder vessels. Int Urogynecol J Pelvic Floor Dysfunct2000;11(2):120 Enskat R, Deaney CN, Glickman S. Systemic effects of intravesicalatropine sulphate. BJU Int 2001;87:613

Eri LM, Tveter KJ. A prospective, placebo-controlled study of theluteinizing hormone-releasing hormone agonist leuprolide astreatment for patients with benign prostatic hyperplasia. J Urol1993;150:359

688

Fader M, Glickman S, Haggar V et al. Intravesical atropinecompared to oral oxybutynin for neurogenic detrusor overactivity:a double-blind, randomized crossover trial. J Urol 2007Jan;177(1)208

Falconer C, Ekman-Ordeberg G, Blomgren B et al. Paraurethralconnective tissue in stress incontinent women after menopause.Acta Obstetr Gynaecol Scand 1998;77(1)95

Fall M, Lindstrom S, Mazieres L. A bladder-to-bladder coolingreflex in the cat. J Physiol, 1990;427:281

Fantl JA, Bump RC, Robinson D et al. Efficacy of estrogensupplementation in the treatment of urinary incontinence. ObstetrGynaecol 1996;88:745

Fantl JA, Cardozo L, McClish DK Estsrogen therapy in themanagement of urinary incontinence in postmenopausal women:a meta –analysis. Frist report of the Hormones and UrogenitalTherapy Committee. Obstet Gynaecol 1996;83:12

Fellenius E, Hedberg R, Holmberg E et al. Functional andmetabolic effects of terbutaline and propranolol in fast and slowcontracting skeletal muscle in vitro. Acta Physiol Scand,1980;109:89

Fetscher C, Fleichman M, Schmidt M et al. M3 muscarinicreceptors mediate contraction of human urinary bladder. Br JPharmacol 2002; 136: 641

Filocamo MT, LiMarzi V, Del Popoilo G et al. Pharmacologictreatment in postprostatectomy stress urinary incontinence. EurUrol 2007;51:1559

Finney SM, Andersson KE, Gillespie JI, Stewart LH. Antimuscarinicdrugs in detrusor overactivity and the overactive bladder syndrome:motor or sensory actions? BJU Int. 2006 Sep;98(3):503

Flicker C, Ferris SH, Serby M. Hypersensitivity to scopolaminein the elderly. Psychopharmacol (Berl) 1992;107:437

Foote J, Glavind K, Kralidis G et al. Treatment of overactivebladder in the older patient: pooled analysis of three phase IIIstudies of darifenacin, an M3 selective receptor antagonist. EurUrol. 2005 Sep;48(3):471

Ford AP, Gever JR, Nunn PA et al. Purinoceptors as therapeutictargets for lower urinary tract dysfunction. Br J Pharmacol. 2006Feb;147 Suppl 2:S132

Fowler CJ, Beck RO, Gerrard S et al. Intravesical capsaicin forthe treatment of detrusor hyperreflexia. J Neurol NeurosurgPsychiatry 1994;57:169

Fowler CJ, Griffiths D, de Groat WC. The neural control ofmicturition. Nat Rev Neurosci. 2008 Jun;9(6):453-66Blok BF,Sturms LM, Holstege G. Brain activation during micturition inwomen. Brain, 1998;121 ( Pt 11):2033

Fowler CJ, Jewkes D, McDonald WI et al. Intravesical capsaicinfor neurogenic bladder dysfunction. Lancet. 1992 May16;339(8803):1239.

Fraser MO, Chancellor MB: Neural control of the urethra anddevelopment of pharmacotherapy for stress urinary incontinence.BJU Int 2003;91(8):743

Frazier EP, Braverman AS, Peters SLM et al. Does phospholipaseC mediate muscarinic receptor-induced rat urinary bladdercontraction? J Pharmacol Exp Ther 2007; 322: 998

Frazier EP, Mathy MJ, Peters SL et al. Does cyclic AMP mediaterat urinary bladder relaxation by isoproterenol? J Pharmacol ExpTher. 2005 Apr;313(1):260

Frazier EP, Peters SLM, Braverman AS et al. Signal transductionunderlying control of urinary bladder smooth muscle tone bymuscarinic receptors and b-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 2008;377: 449

Fredrikson S. Nasal spray desmopressin in treatment of bladderdysfunction in patients with multiple sclerosis. Acta Neurol Scand1996;94:31

Freeman R, Hill S, Millard R et al. Tolterodine Study Group.

Reduced perception of urgency in treatment of overactive bladderwith extended-release tolterodine. Obstet Gynecol2003;102(3):605

Frew R, Lundy PM. A role for Q type Ca2+ channels inneurotransmission in the rat urinary bladder. Br J Pharmacol1995;116:1595

Fröhlich G, Burmeister S, Wiedemann A et al. Intravesicalinstillation of trospium chloride, oxybutynin and verapamil forrelaxation of the bladder detrusor muscle. A placebo controlled,randomized clinical test. Arzneimittelforschung. 1998;May;48(5):486. (German).

Fu X, Rezapour M, Wu X et al. Expression of estrogen receptoralpha and beta in anterior vaginall walls of genuine stressincontinence women. Int Urogynaecol J Pelivc Floor Dysfunc2003;14(4)276, discussion 281

Fujimura T, Tamura K, Tsutsumi T et al. Expression and possiblefunctional role of the beta3-adrenoceptor in human and ratdetrusor muscle. J Urol. 1999 Feb;161(2):680

Fusgen I, Hauri D. Trospium chloride: an effective option formedical treatment of bladder overactivity. Int J Clin PharmacolTher, 2000;38(5):223

Gamé X, Castel-Lacanal E, Bentaleb Y et al. Botulinum toxin Adetrusor injections in patients with neurogenic detrusor overactivitysignificantly decrease the incidence of symptomatic urinary tractinfections. Eur Urol. 2008 Mar;53(3):613

Garely AD, Kaufman JM, Sand PK et al. Symptom bother andhealth-related quality of life outcomes following solifenacintreatment for overactive bladder: the VESIcare Open-Label Trial(VOLT). Clin Ther. 2006 Nov;28(11):1935

Gebhardt J, Richard D, Barrett T. Expression of estrogen receptorisoforms alpha and beta messengera RNA in vaginal tissue ofpremenopausal and postmenopausal women. Am J ObstetrGynaecol 2001;185:1325

Gee NS, Brown JP, Dissanayake VU et al. The novelanticonvulsant drug, gabapentin (Neurontin), binds to thealpha2delta subunit of a calcium channel. J Biol Chem. 1996Mar 8;271(10):5768

Geirsson G, Fall M, Sullivan L. Clinical and urodynamic effectsof intravesical capsaicin treatment in patients with chronic traumaticspinal detrusor hyperreflexia. J Urol. 1995 Nov;154(5):1825

George J, Tharion G, Richar J et al. The effectiveness ofintravesical oxybutynin, propantheline, and capsaicin in themanagement of neuropathic bladder following spinal cord injury.ScientificWorldJournal. 2007 Oct 22;7:1683

Ghoneim GM, Van Leeuwen JS, Elser DM et al. A randomizedcontrolled trial of duloxetine alone, pelvic floor muscle trainingalone, combined treatment, and no treatment in women withstress urinary incontinence. J Urol 2005;173:1647

Giannantoni A, Di Stasi SM, Nardicchi V et al. Botulinum-A toxininjections into the detrusor muscle decrease nerve growth factorbladder tissue levels in patients with neurogenic detrusoroveractivity. J Urol. 2006 Jun;175(6):2341

Giannantoni A, Di Stasi SM, Stephen RL et al. Intravesicalresiniferatoxin versus botulinum-A toxin injections for neurogenicdetrusor overactivity: a prospective randomized study. J Urol2004;172:240

Giannantoni A, Serva MR, Proietti S, et al. Six year follow-up ofintradetrusorial injections of botulinum toxin type A in patientswith refractory neurogenic detrusor overactivity: clinical andurodynamic results - Abstract 567. Eur Urol Supplements.2008;7:212

Giardina EG, Bigger JT. Jr, Glassman AH et al. Theelectrocardiographic and antiarrhythmic effects of imipraminehydrochloride at therapeutic plasma concentrations. Circulation1979;60:1045

Giembycz MA. Life after PDE4: overcoming adverse events with

689

dual-specificity phosphodiesterase inhibitors. Curr OpinPharmacol. 2005 Jun;5(3):238

Gilja I, Radej M, Kovacic M et al. Conservative treatment offemale stress incontinence with imipramine. J Urol 1984;132:909

Gill SS, Mamdani M, Naglie G et al. A prescribing cascadeinvolving cholinesterase inhibitors and anticholinergic drugs. ArchIntern Med 2005;165:808

Gillespie JL. Phosphodiesterase-linked inhibition of nonmicturitionactivity in the isolated bladder. BJU Int. 2004 Jun;93(9):1325

Glazener CMA, Evans JHC. Desmopressin for nocturnal enuresisin children. Cochrane Database Syst Rev 2002;3:CD002112.2008.

Glazener CM, Evans JH, Peto RE. Tricyclic and relarelated drugsfor nocturnal enuresis in children. Cochrane Database Syst Rev2003 (3):CD002117.

Gleason DM, Reilly SA, Bottacini MR, et al. The urethral continencezone and its relation to stress incontinence. J Urol 1974;112:81

Gleason DM, Susset J, White C et al. Evaluation of a new once-daily formulation of oxybutynin the treatment of urinary urgeincontinence. The Ditropan XL Study Group. Urology 1999;54:420

Glickman S, Tsokkos N, Shah PJ. Intravesical atropine andsuppression of detrusor hypercontractility in the neuropathicbladder. A preliminary study. Paraplegia 1995;33:36

Gopalakrishnan M, Shieh C-C. Potassium channel subtypes asmolecular targets for overactive bladder and other urologicaldisorders. Expert Opin Ther Targets 2004; 8: 437

Grady D, Brown JS, Vittinghoff E et al. Postmenopausal hormonesand incontinence: the Heart and Estrogen/Progestin ReplacementStudy. Obstet Gynaecol 2001;97:116

Griffiths DJ Cerebral control of bladder function. Curr Urol Rep,5(5):348, 2004.

Griffiths D. Imaging bladder sensations. Neurourol Urodyn. 2007Oct;26(6 Suppl):899

Holstege G. Micturition and the soul. J Comp Neurol. 2005 Dec5;493(1):15

Griffiths D, Tadic SD. Bladder control, urgency, and urgeincontinence: evidence from functional brain imaging. NeurourolUrodyn. 2008;27(6):466

Griffiths D, Tadic SD, Schaefer W et al. Cerebral control of thebladder in normal and urge-incontinent women. Neuroimage.2007 Aug 1;37(1):1-7

Green SA, Alon A, Ianus J et al. Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactivebladder with urge urinary incontinence. J Urol. 2006 Dec;176(6Pt 1):2535

Grigoleit U, Mürtz G, Laschke S et al. Efficacy, tolerability andsafety of propiverine hydrochloride in children and adolescentswith congenital or traumatic neurogenic detrusor overactivity--aretrospective study. Eur Urol. 2006 Jun;49(6):1114

Grodstein F, Lifford K, Resnick NM et al., Curham GC.Postmenopausal hormone therapy and risk of developing urinaryincontinence. Obstet Gynaecol 2004;103(2):254

Grond S, Sablotzki A. Clinical pharmacology of tramadol. ClinPharmacokinet. 2004;43(13):879

Grosse J, Kramer G, Stöhrer M. Success of repeat detrusorinjections of botulinum a toxin in patients with severe neurogenicdetrusor overactivity and incontinence. Eur Urol. 2005May;47(5):653

Grüneberger A. Treatment of motor urge incontinence withclenbuterol and flavoxate hydrochloride. Br J Obstet Gynaecol1984;91:275

Gu B, Fraser MO, Thor KB et al. Induction of bladder sphincterdyssynergia by k-2 opioid receptor agonists in the female rat. JUrol 2004; 171: 472

Gu BJ, Ishizuka O, Igawa Y et al. Role of supraspinal tachykininsfor micturition in conscious rats with and without bladder outletobstruction. Naunyn Schmiedebergs Arch Pharmacol. 2000May;361(5):543

Guarneri L, Robinson E, Testa R. A review of flavoxate:pharmacology and mechanism of action. Drugs Today, 1994;30:91

Guerra LA, Moher D, Sampson M et al. Intravesical oxybutyninfor children with poorly compliant neurogenic bladder: a systematicreview. J Urol. 2008 Sep;180(3):1091

Guay DR. Clinical pharmacokinetics of drugs used to treat urgeincontinence. Clin Pharmacokinet. 2003;42(14):1243

Gutman GA, Chandy KG, Adelman JP, et al. International Unionof Pharmacology. XLI. Compendium of voltage-gated ion channels:potassium channels. Pharmacol Rev 2003; 55: 583

Haab F, Cardozo L, Chapple C et al. Solifenacin Study Group.Long-term open-label solifenacin treatment associated withpersistence with therapy in patients with overactive bladdersyndrome. Eur Urol. 2005 Mar;47(3):376

Haab F, Corcos J, Siami P et al. Long-term treatment withdarifenacin for overactive bladder: results of a 2-year, open-labelextension study. BJU Int. 2006 Nov;98(5):1025

Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptorantagonist, is an effective and well-tolerated oncedaily treatmentfor overactive bladder. Eur Urol, 2004;45(4):420

Habler HJ, Janig W, Koltzenburg, M. Activation of unmyelinatedafferent fibres by mechanical stimuli and inflammation of theurinary bladder in the cat. J Physiol, 1990;425:545

Haferkamp A, Schurch B, Reitz A et al. Lack of ultrastructuraldetrusor changes following endoscopic injection of botulinumtoxin type a in overactive neurogenic bladder. Eur Urol. 2004Dec; 46(6): 784

Halaska M, Ralph G, Wiedemann A et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerabilityand efficacy of trospium chloride in patients with detrusor instability.2003;World J Urol 20(6):392

Hampel C, Gillitzer R, Pahernik S et al. Medikamentöse Therapieder weiblichen Harninkontinenz. Urologe A 2005; 44: 244

Harper M, Popat RB, Dasgupta R et al. A minimally invasivetechnique for outpatient local anaesthetic administration ofintradetrusor botulinum toxin in intractable detrusor overactivity.BJU Int. 2003 Aug;92(3):325

Haruno A. Inhibitory effects of propiverine hydrochloride on theagonist-induced or spontaneous contractions of various isolatedmuscle preparations. Arzneim-Forsch /Drug Res 1992;42:815

Hashim H, Abrams P. Do symptoms of overactive bladder predicturodynamics detrusor overactivity? NeuroUrol Urodyn2004;23(5/6):484

Hashim H, Abrams P. Pharmacologic management of womenwith mixed urinary incontinence. Drugs 2006;66(5):591

Hashim H and Abrams P. Desmopressin for the treatment ofadult nocturia. Therapy 2008;5:?

Hashim H, Malmberg L, Graugaard-Jensen C et al. Desmopressin,as a "designer-drug," in the treatment of overactive bladdersyndrome. Neurourol Urodyn 2008; in press.

Hashimoto M, Imamura T, Tanimukai S et al. Urinary incontinence:an unrecognised adverse effect with donepezil. Lancet2000;356:568.

Hashimoto S, Kigoshi S, Muramatsu I. Nitric oxidedependentand -independent neurogenic relaxation of isolated dog urethra.Eur J Pharmacol 1993;231: 209

Haustein KO, Huller G. On the pharmacokinetics and metabolismof propiverine in man. Eur J Drug Metab Pharmacokinet1988;13(2):81

Hawthorn MH, Chapple CR, Cock M et al. Urothelium-derivedinhibitory factor(s) influences on detrusor muscle contractility invitro. Br J Pharmacol 2000;129:416

690

Hegde SS. Muscarinic receptors in the bladder: from basicresearch to therapeutics. Br J Pharmacol 2006;147:S80

Hegde SS, Choppin A, Bonhaus D, et al. Functional role of M2and M3 muscarinic receptors in the urinary bladder of rats invitro and in vivo. Br J Pharmacol 1997;120: 1409

Hendrix SL, Cochrane BB, Nygaard IE et al. Effects of estrogenwith and without progestin on urinary incontinence. JAMA2005;293(8):935

Hendrix SL, McNeeley SG. Effect of selective estrogen receptormodulators on reproductive tissues other than endometrium. AnnN Y Acad Sci 2001;949:243

Henriksson L, Andersson K-E, Ulmsten U. The urethral pressureprofiles in continent and stress incontinent women. Scand J UrolNephrol 1979;13:5

Herbison P, Hay-Smith J, Ellis G et al. Effectiveness ofanticholinergic drugs compared with placebo in the treatment ofoveractive bladder: systematic review. Br Med J 2003;326:841

Herschorn S, Gajewski J, Schulz J, Corcos J. A population-basedstudy of urinary symptoms and incontinence: the CanadianUrinary Bladder Survey. BJU Int. 2008 Jan;101(1):52

Hextall A. Oestrogens and lower urinary tract function. Maturitas2000;36:83

Hextall A, Bidmead J, Cardozo L et al. The impact of the menstrualcycle on urinary symptoms and the results of urodynamicinvestigation. BJOG 2001;108(11)1193

Hicks A, McCafferty GP, Riedel E et al. GW427353 (solabegron),a novel, selective beta3-adrenergic receptor agonist, evokesbladder relaxation and increases micturition reflex threshold inthe dog. J Pharmacol Exp Ther. 2007 Oct;323(1):202

Hill S, Khullar V, Wyndaele JJ et al. Dose response withdarifenacin, a novel once-daily M3 selective receptor antagonistfor the treatment of overactive bladder: results of a fixed dosestudy. Int Urogynecol J Pelvic Floor Dysfunct. 2006 May;17(3):239

Hills CJ, Winter SA, Balfour JA. Tolterodine. Drugs 1998;55:813

Hilton P, Hertogs K, Stanton SL. The use of desmopressin(DDAVP) for nocturia in women with multiple sclerosis. J NeurolNeurosurg Psychiatry 1983;46:854

Hilton P, Stanton SL. The use of desmopressin (DDAVP) innocturnal urinary frequency in the female. Br J Urol 1982;54:252

Hilton P, Stanton SL. Urethral pressure measurement bymicrotransducer: the results in symptom free women and in thosewith genuine stress incontinence. Br J Obstet Gynaecol 1983Oct;90(10):919-33.

Hirst GR, Watkins AJ, Guerrero K et al. MG, Botulinum toxin Bis not an effective treatment of refractory overactive bladder.Urology 2007 Jan;69(1):69

Höfner K, Burkart M, Jacob G et al. Safety and efficacy oftolterodine extended release in men with overactive bladdersymptoms and presumed non-obstructive benign prostatichyperplasia. World J Urol. 2007 Dec;25(6):627

Holmes DM, Montz FJ, Stanton SL. Oxybutinin versuspropantheline in the management of detrusor instability. A patientregulated variable dose trial. Br J Obstet Gynaecol 1989;96:607

Hoverd PA, Fowler CJ. Desmopressin in the treatment of daytimeurinary frequency in patients with multiple sclerosis. J NeurolNeurosurg Psychiatry 1998;65:778

Howe BB, Halterman TJ, Yochim CL, et al. Zeneca ZD6169: anovel KATP channel opener with in vivo selectivity for urinarybladder. J Pharmacol Exp Ther 1995; 274: 884

Hruz P, Lövblad KO, Nirkko AC et al. Identification of brainstructures involved in micturition with functional magneticresonance imaging (fMRI). J Neuroradiol. 2008 Jul;35(3):144-9.

Hu S, Kim HS. Modulation of ATP sensitive and large-conductanceCa2+-activated K+ channels by Zeneca ZD6169 in guinea pigbladder smooth muscle cells. J Pharmacol Exp Ther 1997;280:38

Hudman D, Elliott RA, Norman RI. K(ATP) channels mediate thebeta(2)-adrenoceptor agonist-induced relaxation of rat detrusormuscle. Eur J Pharmacol. 2000 May 26;397(1):169

Humeau Y, Doussau F, Grant NJ et al. How botulinum and tetanusneurotoxins block neurotransmitter release. Biochimie. 2000May;82(5):427

Hunsballe JM, Djurhuus JC. Clinical options for imipramine in themanagement of urinary incontinence. Urol Res 2001;29:118

Hughes KM, Lang JCT, Lazare R et al. Measurement of oxybutyninand its N-desethyl metabolite in plasma, and its application topharmacokinetic studies in young, elderly and frail elderlyvolunteers. Xenobiotica, 1992;22:859

Hurley DJ, Turner CL, Yalcin I et al. Duloxetine for the treatmentof stress urinary incontinence: an integrated analysis of safety.Eur J Obstet Gynecol Reprod Biol 2006; 125:120

Hussain RM, Hartigan-Go K, Thomas SHL et al. Effect ofoxybutynin on the QTc interval in elderly patients with urinaryincontinence. Br J Clin Pharmacol 1994;37:485P

Hyman MJ, Groutz A, Blaivas JG. Detrusor instability in men:correlation of lower urinary tract symptoms with urodynamicfindings. J Urol. 2001 Aug;166(2):550

Igawa Y, Komiyama I, Nishizawa O et al. Intravesical capsaicininhibits autonomic dysreflexia in patients with spinal cord injury.Neurourol Urodyn 1996; 15: 374 (abst).

Igawa Y, Yamazaki Y, Takeda H et al. Functional and molecularbiological evidence for a possible beta3-adrenoceptor in thehuman detrusor muscle. Br J Pharmacol. 1999 Feb;126(3):819

Igawa Y, Yamazaki Y, Takeda H et al. Relaxant effects ofisoproterenol and selective beta3-adrenoceptor agonists onnormal, low compliant and hyperreflexic human bladders. J Urol.2001 Jan;165(1):240

Iijima K, De Wachter S, Wyndaele JJ. Effects of the M3 receptorselective muscarinic antagonist darifenacin on bladder afferentactivity of the rat pelvic nerve. Eur Urol. 2007 Sep;52(3):842

Insel PA, Tang C-M, Hahntow I et al. Impact of GPCRs in clinicalmedicine: genetic variants and drug targets. Biochim BiophysActa 2007;1768:994

Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S,Coyne K, Kelleher C, Hampel C, Artibani W, Abrams P. Population-based survey of urinary incontinence, overactive bladder, and otherlower urinary tract symptoms in five countries: results of the EPICstudy. Eur Urol. 2006 Dec;50(6):1306

Ishiko O, Hirai K, Sumi T et al. Hormone replacement therapy pluspelvic floor muscle exercise for postmenopausal stsressincontinence. A randomized controlled trial, J Reprod Med2001;46:213

Ishiko O, Ushiroyama T, Saji F et al. Beta(2)-Adrenergic agonistsand pelvic floor exercises for female stress incontinence. Int JGynaecol Obstet 2000;71:39

Ishizuka O, Igawa Y, Lecci A et al. Role of intrathecal tachykininsfor micturition in unanaesthetized rats with and without bladderoutlet obstruction. Br J Pharmacol. 1994 Sep;113(1):111

Ishizuka O, Igawa Y, Nishizawa O et al. Role of supraspinaltachykinins for volume- and L-dopa-induced bladder activity innormal conscious rats. Neurourol Urodyn. 2000;19(1):101

Ishizuka O, Mattiasson A, Andersson KE. Effects of neurokininreceptor antagonists on L-dopa induced bladder hyperactivity innormal conscious rats. J Urol. 1995 Oct;154(4):1548

Jackson S, Shepherd A, Abrams P. The effect of oestradiol onobjective urinary leakage in postmenopausal stress incontinence:a double blind placebo controlled trial. Neurourol Urodyn199615:322

Janig W, Morrison JF. Functional properties of spinal visceralafferents supplying abdominal and pelvic organs, with specialemphasis on visceral nociception. Prog Brain Res, 1986;67:87

691

Jeremy JY, Tsang V, Mikhailidis DP et al. Eicosanoid synthesisby human urinary bladder mucosa: pathological implications. BrJ Urol 1987;59:36

Johnson TMII, Miller M, Tang T et al. Oral ddAVP for nighttimeurinary incontinence in characterized nursing home residents: apilot study. J Am Med Dir Assoc 2006;7:6

Jünemann KP, Al-Shukri S. Efficacy and tolerability of trospiumchloride and tolterodine in 234 patients with urge-syndrome: adouble-blind, placebo-controlled multicentre clinical trial. NeurourolUrodyn 2000;19:488

Jünemann KP, Halaska M, Rittstein T et al. Propiverine versustolterodine: efficacy and tolerability in patients with overactivebladder. Eur Urol. 2005 Sep;48(3):478

Jünemann KP, Hessdörfer E, Unamba-Oparah I et al. Propiverinehydrochloride immediate and extended release: comparison ofefficacy and tolerability in patients with overactive bladder. UrolInt. 2006;77(4):334

Kachur JF, Peterson JS, Carter JP et al. R and S enantiomersof oxybutynin: pharmacological effects in guinea pig bladder andintestine. J Pharmacol Exp Ther, 1988;247: 867

Kaidoh K, Igawa Y, Takeda H et al. Effects of selective beta2and beta3-adrenoceptor agonists on detrusor hyperreflexia inconscious cerebral infarcted rats. J Urol. 2002 Sep;168(3):1247

Kaiho Y, Nishiguchi J, Kwon DD et al. The effects of a type 4phosphodiesterase inhibitor and the muscarinic cholinergicantagonist tolterodine tartrate on detrusor overactivity in femalerats with bladder outlet obstruction. BJU Int. 2008 Mar;101(5):615

Kaisary AV. Beta adrenoceptor blockade in the treatment offemale stress urinary incontinence. J d’Urol (Paris) 1984;90:351

Kajbafzadeh AM, Moosavi S, Tajik P et al. Intravesical injectionof botulinum toxin type A: management of neuropathic bladderand bowel dysfunction in children with myelomeningocele. Urology,2006 Nov; 68(5):1091

Kalsi V, Apostolidis A, Gonzales G et al. Early effect on theoveractive bladder symptoms following botulinum neurotoxintype A injections for detrusor overactivity. Eur Urol. 2008Jul;54(1):181

Kalsi V, Gonzales G, Popat R et al. Botulinum injections for thetreatment of bladder symptoms of multiple sclerosis. Ann Neurol.2007 Nov;62(5):452

Kalsi V, Popat RB, Apostolidis A et al. Cost-consequence analysisevaluating the use of botulinum neurotoxin-A in patients withdetrusor overactivity based on clinical outcomes observed at asingle UK centre.Eur Urol. 2006 Mar; 49(3):519Kamo I, Chancellor MB, De Groat WC et al. Differential effectsof activation of peripheral and spinal tachykinin neurokinin3receptors on the micturition reflex in rats. J Urol 2005; 174: 776 Kaplan SA, Roehrborn CG, Rovner ES et al. Tolterodine andtamsulosin for treatment of men with lower urinary tract symptomsand overactive bladder: a randomized controlled trial. JAMA 2006Nov 15;296(19):2319 Kaplan SA, Roehrborn CG, Chancellor M et al. Extended-releasetolterodine with or without tamsulosin in men with lower urinarytract symptoms and overactive bladder: effects on urinarysymptoms assessed by the International Prostate SymptomScore. BJU Int. 2008b May 26. [Epub ahead of print]Kaplan SA, Walmsley K, Te AE. Tolterodine extended releaseattenuates lower urinary tract symptoms in men with benignprostatic hyperplasia. J Urol. 2008a May;179(5 Suppl):S82 Karsenty G, Boy S, Reitz A et al. Botulinum toxin A (BTA) in thetreatment of neurogenic detrusor overactivity incontinence (NDOI)-a prospective randomized study to compare 30 vs 10 injectionssites. Neururol Urodyn. 2005: 24 (5/6): 547-548 (abstract 93).

Karsenty G, Denys P, Amarenco G, et al.. Botulinum toxin A(Botox) intradetrusor injections in adults with neurogenic detrusoroveractivity/neurogenic overactive bladder: a systematic literaturereview. Eur Urol. 2008 Feb;53(2):275

Karsenty G, Elzayat E, Delapparent T et al. Botulinum toxin typea injections into the trigone to treat idiopathic overactive bladderdo not induce vesicoureteral reflux. J Urol. 2007 Mar;177(3):1011

Kasabian NG, Vlachiotis JD, Lais A et al. The use of intravesicaloxybutynin chloride in patients with detrusor hypertonicity anddetrusor hyperreflexia. J Urol 1994;151:944

Katofiasc MA, Nissen J, Audia JE, et al: Comparison of the effectsof serotonin selective norepinephrine selective, and dual serotoninand norepinephrine reuptake inhibitors on lower urinary tractfunction in cats. Life Sci 2002;71(11):1227

Katz IR, Prouty Sands L, Bilker W et al. Identification of medicationsthat cause cognitive impairment in older people: the case ofoxybutynin chloride. J Am Geriatr Soc 1998;46:8

Kay G, Crook T, Rekeda L et al. Differential effects of theantimuscarinic agents darifenacin and oxybutynin ER on memoryin older subjects. Eur Urol. 2006 Aug;50(2):317

Kay GG, Ebinger U. Preserving cognitive function for patients withoveractive bladder: evidence for a differential effect withdarifenacin. Int J Clin Pract. 2008 Aug 11. [Epub ahead of print]

Kay GG, Wesnes KA. Pharmacodynamic effects of darifenacin,a muscarinic M selective receptor antagonist for the treatment ofoveractive bladder, in healthy volunteers.

BJU Int. 2005 Nov;96(7):1055

Klausner AP, Steers WD. Antimuscarinics for the treatment ofoveractive bladder: a review of central nervous system effects.Curr Urol Rep. 2007 Nov;8(6):441

Keane DP, Sims TJ, Abrams P et al. Analysis of collagen statusin premenopausal nulliparous women with genuine stressincontinence. Br J Obstet and Gynaecol 1997;104(9)994

Kelleher C, Cardozo L, Kobashi K et al. Solifenacin: as effectivein mixed urinary incontinence as in urge urinary incontinence. IntUrogynecol J Pelvic Floor Dysfunct. 2006 Jun;17(4):382

Kelleher CJ, Tubaro A, Wang JT et al. Impact of fesoterodine onquality of life: pooled data from two randomized trials. BJU Int.2008 Jul;102(1):56 Kennedy C, Tasker PN, Gallacher G et al. Identification of atropine-and P2X1 receptor antagonist-resistant, neurogenic contractionsof the urinary bladder. J Neurosci 2007 Jan 24;27(4):845 Kerbusch T, Wahlby U, Milligan PA et al. M.O. Populationpharmacokinetic modelling of darifenacin and its hydroxylatedmetabolite using pooled data, incorporating saturable first-passmetabolism, CYP2D6 genotype and formulation-dependentbioavailability. Br J Clin Pharmacol 2003;56(6):639

Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamineand the risk of hemorrhagic stroke. N Engl J Med 200;343(25):1826

Kessler TM, Studer UE, Burkhard FC. The effect of terazosin onfunctional bladder outlet obstruction in women: a pilot study. J Urol.2006 Oct;176(4 Pt 1):1487

Khera M, Somogyi GT, Kiss S et al. Botulinum toxin A inhibits ATPrelease from bladder urothelium after chronic spinal cord injury.Neurochem Int. 2004 Dec;45(7):987Khullar V, Rovner ES, Dmochowski R et al. Fesoterodine doseresponse in subjects with overactive bladder syndrome. Urology.2008 May;71(5):839Kim YH, Bird ET, Priebe M et al. The role of oxybutynin in spinalcord injured patients with indwelling catheters. J Urol1996;158:2083 Kim YT, Kwon DD, Kim J et al. Gabapentin for overactive bladderand nocturia after anticholinergic failure. Int Braz J Urol. 2004 Jul-Aug;30(4):275

Kim YS, Sainz RD. Beta adrenergic agonists and hypertrophy ofskeletal muscles. Life Sci 1992;50:397

Kim Y, Yoshimura N, Masuda H et al.: Intravesical instillation ofhuman urine after oral administration of trospium, tolterodineand oxybutynin in a rat model of detrusor overactivity. BJU Int 2006,97:400

692

Kinn AC, Larsson PO. Desmopressin: a new principle forsymptomatic treatment of urgency and incontinence in patientswith multiple sclerosis. Scand J Urol Nephrol 1990;24:109

Kishimoto T, Morita T, Okamiya Y et al. Effect of clenbuterol oncontractile response in periurethral striated muscle of rabbits.Tohoko J Exp Med 1991;165(3):243

Kories C, Czyborra C, Fetscher C et al. Gender comparison ofmuscarinic receptor expression and function in rat and humanurinary bladder: differential regulation of M2 and M3? Naunyn-Schmiedeberg's Arch Pharmacol 2003;367:524

Kuipers M, Tran D, Krauwinkel W et al. Absolute bioavailabilityof YM905 in healthy male volunteers. A single-dose randomized,two-period crossover study. Presented at the 32nd InternationalContinence Society Annual Meeting, Heidelberg, Germany, August2002

Kumar V, Cross RL, Chess-Williams R et al. Recent advancesin basic science for overactive bladder. Curr Opin Urol 2005;15:222

Kuo HC. Effectiveness of intravesical resiniferatoxin in treatingdetrusor hyper-reflexia and external sphincter dyssynergia inpatients with chronic spinal cord lesions. BJU Int. 2003Oct;92(6):597

Kuo HC. Clinical effects of suburothelial injection of botulinum Atoxin on patients with nonneurogenic detrusor overactivityrefractory to anticholinergics. Urology. 2005 Jul;66(1):94

Kuo HC, Multiple intravesical instillation of low-dose resiniferatoxinis effective in the treatment of detrusor overactivity refractory toanticholinergics. BJU Int. 2005 May;95(7):1023

Kuo HC. Comparison of effectiveness of detrusor, suburothelialand bladder base injections of botulinum toxin a for idiopathicdetrusor overactivity. J Urol. 2007 Oct;178(4 Pt 1):1359

Kuo HC, Liu HT, Yang WC. Therapeutic effect of multipleresiniferatoxin intravesical instillations in patients with refractorydetrusor overactivity: a randomized, double-blind, placebocontrolled study. J Urol. 2006 Aug;176(2):641

Larsen JJ. alpha And beta-adrenoceptors in the detrusor muscleand bladder base of the pig and beta-adrenoceptors in the detrusormuscle of man. Br J Pharmacol 1979;65(2):215

Lazzeri M, Beneforti P, Turini D, Urodynamic effects of intravesicalresiniferatoxin in humans: preliminary results in stable and unstabledetrusor. J Urol 1997 Dec;158(6):2093

Lazzeri M, Spinelli M, Beneforti P et al. Intravesical resiniferatoxinfor the treatment of detrusor hyperreflexia refractory to capsaicinin patients with chronic spinal cord diseases. Scand J UrolNephrol. 1998 Sep;32(5):331

Lee KS, Choo MS, Kim DY et al. Combination treatment withpropiverine hydrochloride plus doxazosin controlled releasegastrointestinal therapeutic system formulation for overactivebladder and coexisting benign prostatic obstruction: a prospective,randomized, controlled multicenter study. J Urol. 2005 Oct;174(4Pt 1):1334

Lee JY, Kim HW, Lee SJ et al.Comparison of doxazosin with orwithout tolterodine in men with symptomatic bladder outletobstruction and an overactive bladder. BJU Int. 2004 Oct;94(6):817

Lee KS, Lee HW, Han DH. Does anticholinergic medication havea role in treating men with overactive bladder and benign prostatichyperplasia? Naunyn Schmiedebergs Arch Pharmacol. 2008Jun;377(4-6):491

Leslie CA, Pavlakis AJ, Wheeler JS Jr et al. Release ofarachidonate cascade products by the rabbit bladder:neurophysiological significance? J Urol 1984;132:376

Lin HH, Sheu BC, Lo MC et al. Comparison of treatment outcomesfor imipramine for female genuine stress incontinence. Br J ObstetGynaecol 1999;106:1089

Lincoln J, Burnstock G. Autonomic innervation of the urinarybladder and urethra. In The Autonomic Nervous System. Vol. 6,Chapter 2, Nervous Control of the Urogenital System, ed. CA

Maggi, London: Harwood Academic Publisher, p. 33, 1993.

Liu HT, Chancellor MB, Kuo HC. Urinary nerve growth factorlevels are elevated in patients with detrusor overactivity anddecreased in responders to detrusor botulinum toxin-A injection.Eur Urol. 2008 Apr 30.

Liu HT, Kuo HC, Increased expression of transient receptorpotential vanilloid subfamily 1 in the bladder predicts the responseto intravesical instillations of resiniferatoxin in patients withrefractory idiopathic detrusor overactivity. BJU Int. 2007Nov;100(5):1086

Lecci A, Maggi CA. Tachykinins as modulators of the micturitionreflex in the central and peripheral nervous system. Regul Pept.2001 Sep 15;101(1-3):1

Leon LA, Hoffman BE, Gardner SD et al. Effects of the beta 3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on bladder micturition reflex inspontaneously hypertensive rats. J Pharmacol Exp Ther. 2008Jul;326(1):178

Leung FP, Yung LM, Yao X et al. Store-operated calcium entryin vascular smooth muscle. Br J Pharmacol 2008; 153: 846

Lindholm P, Lose G. Terbutaline (Bricanyl) in the treatment offemale urge incontinence. Urol Int 1986;41(2):158

Lipton RB, Kolodner K, Wesnes K. Assessment of cognitivefunction of the elderly population: effects of darifenacin. J Urol.2005 Feb;173(2):493

Longhurst PA, Briscoe JA, Rosenberg DJ et al. The role of cyclicnucleotides in guinea-pig bladder contractility. Br J Pharmacol.1997 Aug;121(8):1665

Lose G, Jorgensen L, Thunedborg P. Doxepin in the treatmentof female detrusor overactivity: A randomized double-blindcrossover study. J Urol 1989;142:1024

Lose G, Lalos O, Freeman RM et al. Efficacy of desmopressin(Minirin) in the treatment of nocturia: a double-blind placebo-controlled study in women. Am J Obstet Gynecol 2003;189:1106

Lose G, Mattiasson A, Walter S et al. Clinical experience withdesmopressin for long-term treatment of nocturia. J Urol2004;172:1021

Lose G, Norgaard JP. Intravesical oxybutynin for treatingincontinence resulting from an overactive detrusor. BJU Int2001;87:767

Low BY, Liong ML, Yuen KH et al. Terazosin therapy for patientswith female lower urinary tract symptoms: A randomized, double-blind, placebo controlled trial . J Urol. 2008 Apr;179(4):1461

Lucioni A, Bales GT, Lotan TL et al. Botulinum toxin type A inhibitssensory neuropeptide release in rat bladder models of acuteinjury and chronic inflammation. BJU Int. 2008 Feb;101(3):366 .

Nitti VW, Dmochowski R, Sand PK et al. Efficacy, safety andtolerability of fesoterodine for overactive bladder syndrome. JUrol. 2007 Dec;178(6):2488

Nour S, Svarer C, Kristensen JK et al. Cerebral activation duringmicturition in normal men. Brain, 2000;123 (Pt 4):781

Madersbacher H, Halaska M, Voigt R et al. A placebo-controlled,multicentre study comparing the tolerability and efficacy ofpropiverine and oxybutynin in patients with urgency and urgeincontinence. BJU Int 1999;84:646

Madersbacher H, Mürz G. Efficacy, tolerability and safety profileof propiverine in the treatment of the overactive bladder (non-neurogenic and neurogenic). World J Urol, 2001;19:324

Madersbacher H, Stohrer M, Richter R ET AL. Trospium chlorideversus oxybutynin: a randomized, double-blind, multicentre trialin the treatment of detrusor hyper-reflexia. Br J Urol1995;75(4):452

Maggi CA, Borsini F, Lecci A et al. The effect of acute and chronicadministration of imipramine on spinal and supraspinal micturitionreflexes in rats. J Pharmacol Exp Ther, 1989;248:278

693

Malhotra BK, Glue P, Sweeney K et al. Thorough QT study withrecommended and supratherapeutic doses of tolterodine. ClinPharmacol Ther. 2007 Mar;81(3):377

Malone-Lee JG, Walsh JB, Maugourd MF et al. Tolterodine: a safeand effective treatment for older patients with overactive bladder.J Am Geriatr Soc 2001;49:700

Maneuf YP, Gonzalez MI, Sutton KS et al. Cellular and molecularaction of the putative GABA-mimetic, gabapentin. Cell Mol LifeSci. 2003 Apr;60(4):742

Maniscalco M, Singh-Franco D, Wolowich WR et al. Solifenacinsuccinate for the treatment of symptoms of overactive bladder.Clin Ther. 2006 Sep;28(9):1247

Mansfield KJ, Liu L, Mitchelson FJ et al. Muscarinic receptorsubtypes in human bladder detrusor and mucosa, studied byradioligand bindingand quantitative competitive RT-PCR: changesin ageing. Br J Pharmacol 2005;144:1089

Mariappan P, Ballantyne Z, N’Dow JMO et al: Serotonin andnoradrenaline reuptake inhibitors (SNRI) for stress urinaryincontinence in adults (review). Cochrane Database of SystemicReviews 2005, Issue 3, Art. No: CD 004742. DOI:10.1002/14651858. CD 0043742. pub 2. Also published in TheCochrane Library 2007, issue 3

Marschall-Kehrel D, Feustel C, Persson de Geeter C et al.Treatment with propiverine in children suffering fromnonneurogenic overactive bladder and urinary incontinence:results of a randomized placebo-controlled phase 3 clinical trial.Eur Urol. 2008 May 7. [Epub ahead of print]

Martin SW, Radley SC, Chess-Williams R et al. Relaxant effectsof potassium-channel openers on normal and hyper-reflexicdetrusor muscle. Br J Urol 1997; 80: 405

Martin MR, Schiff AA. Fluphenazine/nortriptyline in the irritativebladder syndrome: a double-blind placebo-controlled study. Br JUrol 1984;56:178

Mascarenhas F, Cocuzza M, Gomes CM et al. Trigonal injectionof botulinum toxin-A does not cause vesicoureteral reflux inneurogenic patients. Neurourol Urodyn. 2008;27(4):311

Massaro AM, Lenz KL. Aprepitant: a novel antiemetic forchemotherapy-induced nausea and vomiting. Ann Pharmacother.2005 Jan;39(1):77

Mattiasson A, Abrams P, van Kerrebroeck P et al. Efficacy ofdesmopressin in the treatment of nocturia: a double-blind placebo-controlled study in men. BJU Int 2002;89:855

Mattiasson A, Blaakaer J, Hoye K et al. Tolterodine ScandinavianStudy Group. Simplified bladder training augments theeffectiveness of tolterodine in patients with an overactive bladder.BJU Int 2003;91(1):54

Matsui M, Griffin MT, Shehnaz D et al. Increased relaxant actionof forskolin and isoproterenol against muscarinic agonist-inducedcontractions in smooth muscle from M2 receptor knockout mice.J Pharmacol Exp Ther 2003; 305:106

Matsui M, Motomura D, Fujikawa T, et al. Mice lacking M2 andM3 muscarinic acetylcholine receptors are devoid of cholinergicsmooth muscle contractions but still viable. J Neurosci 2002;22:10627

Matthiesen TB, Rittig S, Norgaard JP et al. Nocturnal polyuria andnatriuresis in male patients with nocturia and lower urinary tractsymptoms. J Urol 1996;156:1292

Matsui M, Motomura D, Karasawa H et al. Multiple functionaldefects in peripheral autonomic organs in mice lacking muscarinicacetylcholine receptor gene for the M3 subtype. Proc Natl AcadSci USA 2000;97:9579

May K, Westphal K, Giessmann T et al. Disposition andantimuscarinic effects of the urinary bladder spasmolyticspropiverine: influence of dosage forms and circadian-time rhythms.J Clin Pharmacol. 2008 May;48(5):570

McConnell JD, Roehrborn CG, Bautista OM et al. Medical Therapy

of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy onthe clinical progression of benign prostatic hyperplasia. N EnglJ Med. 2003 Dec 18;349(25):2387

McCrery RJ, Appell RA. Oxybutynin: an overview of the availableformulations. Ther Clin Risk Manag. 2006 Mar;2(1):19

McNeill SA, Hargreave TB. Alfuzosin once daily facilitates returnto voiding in patients in acute urinary retention. J Urol2004;171:2316

McNeill SA, Hargreave TB, Roehrborn CG. Alfuzosin 10 mg oncedaily in the management of acute urinary retention: results of adouble-blind placebo-controlled study. Urology 2005;65:83

McVary KT, Monnig W, Camps JL Jr et al. Sildenafil citrateimproves erectile function and urinary symptoms in men witherectile dysfunction and lower urinary tract symptoms associatedwith benign prostatic hyperplasia: a randomized, double-blindtrial. J Urol. 2007b Mar;177(3):1071

McVary KT, Roehrborn CG, Kaminetsky JC et al. Tadalafil relieveslower urinary tract symptoms secondary to benign prostatichyperplasia. J Urol. 2007a Apr;177(4):1401

Mehnert U, Boy S, Svensson J et al. Brain activation in responseto bladder filling and simultaneous stimulation of the dorsal clitoralnerve - an fMRI study in healthy women. Neuroimage 2008 Jul1;41(3):682-9.

Menarini M, Del Popolo G, Di Benedetto P et al. Trospium chloridein patients with neurogenic detrusor overactivity: is dose titrationof benefit to the patients? Int J Clin Pharmacol Ther. 2006Dec;44(12):623

Meng J, Wang J, Lawrence G et al. Synaptobrevin I mediatesexocytosis of CGRP from sensory neurons and inhibition bybotulinum toxins reflects their anti-nociceptive potential J CellSci. 2007 Aug 15;120(Pt 16):2864

Michel MC. Fesoterodine: a novel muscarinic receptor antagonistfor the treatment of overactive bladder syndrome. Expert OpinPharmacother. 2008 Jul;9(10):1787

Michel MC, Barendrecht MM. Physiological and pathologicalregulation of the autonomic control of urinary bladder contractility.Pharmacol Ther 2008;117:297

Michel MC, Hegde SS. Treatment of the overactive bladdersyndrome with muscarinic receptor antagonists: a matter ofmetabolites? Naunyn Schmiedebergs Arch Pharmacol. 2006Nov;374(2):79

Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptorsin the urinary bladder, urethra and prostate. Br J Pharmacol.2006 Feb;147 Suppl 2:S88

Michel MC, Wetterauer U, Vogel M et al. Cardiovascular safetyand overall tolerability of solifenacin in routine clinical use: a 12-week, open-label, post-marketing surveillance study. Drug Saf.2008;31(6):505

Milani R, Scalambrino S, Milia R et al. Double-blind crossovercomparison of flavoxate and oxybutynin in women affected byurinary urge syndrome. Int Urogynecol J, 1993;4:3

Millard RJ. Asia Pacific Tolterodine Study Group. Clinical efficacyof tolterodine with or without a simplified pelvic floor exerciseregimen. Neurourol Urodyn 2004;23(1):48

Millard RJ, Moore K, Rencken R et al. Duloxetine versus placeboin the treatment of stress urinary incontinence: a four continentrandomized clinical trial. BJU Int 2004;93:311

Miyazato M, Sasatomi K, Hiragata S et al. Suppression of detrusor-sphincter dysynergia by GABA-receptor activation in thelumbosacral spinal cord in spinal cord-injured rats. Am J PhysiolRegul Integr Comp Physiol. 2008a Jul;295(1):R336

Miyazato M, Sasatomi K, Hiragata S et al. GABA receptoractivation in the lumbosacral spinal cord decreases detrusoroveractivity in spinal cord injured rats. J Urol. 2008b Mar;179(3):1178

694

Morelli A, Vignozzi L, Filippi S et al. BXL-628, a vitamin D receptoragonist effective in benign prostatic hyperplasia treatment,prevents RhoA activation and inhibits RhoA/Rho kinase signalingin rat and human bladder. Prostate. 2007 Feb 15;67(3):234

Morenilla-Palao C, Planells-Cases R, García-Sanz N et al.Regulated exocytosis contributes to protein kinase C potentiationof vanilloid receptor activity. Biol Chem. 2004 Jun 11;279(24):25665

Morita T, Ando M, Kihara K, et al. Effects of prostaglandins E1,E2 and F2alpha on contractility and cAMP and cGMP contentsin lower urinary tract smooth muscle. Urol Int 1994;52:200

Morita T, Iizuka H, Iwata T et al. Function and distribution ofbeta3-adrenoceptors in rat, rabbit and human urinary bladderand external urethral sphincter. J Smooth Muscle Res. 2000Feb;36(1):21

Mostwin J, Bourcier A, Haab F et al. Pathophysiology of urinaryincontinence, fecal incontinence and pelvic organ prolapse. In,Abrams P, Cardozo L, Khoury S, Wein A (eds): Incontinence.Plymouth, UK, Health Publications, pp 423, 2005

Muller C, Siegmund W, Huupponen R et al. Kinetics of propiverineas assessed by radioreceptor assay in poor and extensivemetabolizers of debrisoquine. Eur J Drug Metab Pharmacokinet1993;18(3):265

Murakami S, Chapple CR, Akino H et al. The role of the urotheliumin mediating bladder responses to isoprenaline. BJU Int. 2007Mar;99(3):669

Muskat Y, Bukovsky I, Schneider D et al. The use of scopolaminein the treatment of detrusor instability. 1996;J Urol 156:1989

Musselman DM, Ford AP, Gennevois DJ, et al. A randomizedcrossover study to evaluate Ro 115-1240, a selective alpha 1 A/1L-adrenoceptor partial agonist in women with stress urinaryincontinence. BJU Int 2004Jan;93(1):78

Naglie G, Radomski SB, Brymer C et al. A randomized, double-blind, placebo controlled crossover trial of nimodipine in olderpersons with detrusor instability and urge incontinence. J Urol2002;167:586

Naglo AS, Nergardh A, Boreus LO. Influence of atropine andisoprenaline on detrusor hyperactivity in children with neurogenicbladder. Scand J Urol Nephrol 1981;15(2):97

Nergardh A, Boreus LO, Naglo AS. Characterization of theadrenergic beta-receptor in the urinary bladder of man and cat.Acta Pharmacol Toxicol (Copenh) 1977;40(1):14

Neveus T, Tullus K. Tolterodine and imipramine in refractoryenuresis: a placebo-controlled crossover study. Pediatr Nephrol2008;23:263

Ney P, Pandita RK, Newgreen DT et al. Pharmacologicalcharacterization of a novel investigational antimuscarinic drug,fesoterodine, in vitro and in vivo. BJU Int. 2008 Apr;101(8):1036

Nilvebrant L, Andersson K-E, Gillberg PG. Tolterodine—a newbladder-selective antimuscarinic agent. Eur J Pharmacol,1997b;327(2-3):195

Nilvebrant L, Andersson K-E, Mattiasson A. Characterization ofthe muscarinic cholinoceptors in the human detrusor. J Urol1985;134: 418

Nilvebrant L, Gillberg PG, Sparf B. Antimuscarinic potency andbladder selectivity of PNU-200577, a major metabolite oftolterodine. Pharmacol Toxicol, 1997a;81(4):169

Nilvebrant L, Sparf B. Dicyclomine, benzhexol and oxybutynindistinguish between subclasses of muscarinic binding sites. EurJ Pharmacol 1986;123:133

Nishiguchi J, Kwon DD, Kaiho Y et al. Suppression of detrusoroveractivity in rats with bladder outlet obstruction by a type 4phosphodiesterase inhibitor. BJU Int. 2007 Mar;99(3):680

Nitti VW. Botulinum toxin for the treatment of idiopathic andneurogenic overactive bladder: state of the art Rev Urol. 2006Fall;8(4):198

Noguchi M, Eguchi Y, Ichiki J et al. Therapeutic efficacy ofclenbuterol for urinary incontinence after radical prostatectomy.Int J Urol 1997;4:480

Nomiya M, Yamaguchi O. A quantitative analysis of mRNAexpression of alpha 1 and beta-adrenoceptor subtypes and theirfunctional roles in human normal and obstructed bladders. JUrol. 2003 Aug;170(2 Pt 1):649

Norhona-Blob L, Kachur JF. Enantiomers of oxybutynin: in vitropharmacological characterization at M1, M2 and M3 muscarinicreceptors and in vivo effects on urinary bladder contraction,mydriasis and salivary secretion in guinea pigs. J PharmacolExp Ther 1991;256:562

Norton PA, Zinner NR, Yalcin I et al. Duloxetine versus placeboin the treatment of stress urinary incontinence. Am J ObstetGynecol 2002;187:40

Novara G, Galfano A, Secco S et al. Systematic Review andMeta-Analysis of Randomized Controlled Trials with AntimuscarinicDrugs for Overactive Bladder. Eur Urol. 2008 Jul 9.

Obenchain R, Swindle R. Impact of duloxetine on quality of lifefor women with symptoms of urinary incontinence. 2005;16:337

Oka M, Kimura,Y, Itoh Y et al. Brain pertussis toxin-sensitive Gproteins are involved in the flavoxate hydrochloride-inducedsuppression of the micturition reflex in rats. Brain Res 1996;727(1-2):91

Olshansky B, Ebinger U, Brum J et al. Differential pharmacologicaleffects of antimuscarinic drugs on heart rate: A randomized,placebo-controlled, double-blind, crossover study with tolterodineand darifenacin in healthy participants >=50 Years. J CardiovascPharmacol Ther. 2008 Dec; 13(4):241

Otsuka A, Shinbo H, Matsumoto R et al. Expression and functionalrole of beta-adrenoceptors in the human urinary bladderurothelium. Naunyn Schmiedebergs Arch Pharmacol. 2008Jun;377(4-6):473

Ouslander JG. Management of overactive bladder. New Engl JMed, 350:786, 2004.

Ouslander JG, Blaustein J, Connor A et al. Pharmacokineticsand clinical effects of oxybutynin in geriatric patients. J Urol1988;140:47

Ouslander JG, Schnelle JF, Uman G et al. Does oxybutynin addto the effectiveness of prompted voiding for urinary incontinenceamong nursing home residents? A placebo-controlled trial. J AmGeriatr Soc 1995;43:610

Palea S, Artibani, W, Ostardo, E et al. Evidence for purinergicneurotransmission in human urinary bladder affected by interstitialcystitis. J Urol, 1993;150(6):2007

Palmer J. Report of a double-blind crossover study of flurbiprofenand placebo in detrusor instability. J Int Med Res 1983;11Supplement 2:11

Patel AK, Patterson JM, Chapple CR. Botulinum toxin injectionsfor neurogenic and idiopathic detrusor overactivity: A criticalanalysis of results. Eur Urol. 2006 Oct;50(4):684

Palmer LS, Zebold K, Firlit CF et al. Complications of intravesicaloxybutynin chloride therapy in the pediatric myelomeningocelepopulation. J Urol 1997;157:638

Pehrson R, Andersson KE. Tramadol inhibits rat detrusoroveractivity caused by dopamine receptor stimulation. J Urol.2003 Jul;170(1):272

Pehrson R, Andersson KE. Effects of tiagabine, a gamma-aminobutyric acid re-uptake inhibitor, on normal rat bladderfunction. J Urol. 2002 May;167(5):2241

Pehrson R, Stenman E, Andersson KE. Effects of tramadol onrat detrusor overactivity induced by experimental cerebralinfarction. Eur Urol. 2003 Oct;44(4):495

Peters SL, Schmidt M, Michel MC. Rho kinase: a target fortreating urinary bladder dysfunction? Trends Pharmacol Sci.2006 Sep;27(9):492

695

Peters CA, Walsh PC. The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatichyperplasia. N Engl J Med 1987;317:599.

Pistolesi D, Selli C, Rossi B et al. Botulinum toxin type B for typeA resistant bladder spasticity. J Urol. 2004 Feb;171(2 Pt 1):802

Pontari MA, Braverman AS, Ruggieri MR, Sr. The M2 muscarinicreceptor mediates in vitro bladder contractions from patients withneurogenic bladder dysfunction. Am J Physiol 2004;286:R874

Popat R, Apostolidis A, Kalsi V et al. A comparison between theresponse of patients with idiopathic detrusor overactivity andneurogenic detrusor overactivity to the first intradetrusor injectionof botulinum-A toxin. J Urol. 2005 Sep;174(3):984

Purkiss J, Welch M, Doward S et al. Capsaicin-stimulated releaseof substance P from cultured dorsal root ganglion neurons:involvement of two distinct mechanisms. Biochem Pharmacol.2000 Jun 1;59(11):1403

Radley SC, Chapple CR, Bryan NP et al. Effect of methoxamineon maximum urethral pressure in women with genuine stressincontinence: a placebo-controlled, double-blind crossover study.Neurourol Urodyn 2001;20(1):43

Radziszewski P, Borkowski A, Botulinum toxin type A intravesicalinjections for intractable bladder overactivity. Eur Urol Suppl,2002;1(1):134.

Rapp DE, Lucioni A, Katz EE et al. Use of botulinum-A toxin forthe treatment of refractory overactive bladder symptoms: aninitial experience. Urology. 2004 Jun;63(6):1071

Rapp DE, Lyon MB, Bales GT et al. A role for the P2X receptorin urinary tract physiology and in the pathophysiology of urinarydysfunction. Eur Urol 2005;48:303

Rapp DE, Turk KW, Bales GT et al. Botulinum toxin type a inhibitscalcitonin gene-related peptide release from isolated rat bladder.J Urol. 2006 Mar;175(3 Pt 1):1138

Raz S, Zeigler M, Caine M. The effect of progesterone on theadrenergic receptors of the urethra. Br J Urol 1973;45(2)131

Reitz A, Denys P, Fermanian C et al. Do repeat intradetrusorbotulinum toxin type a injections yield valuable results? Clinicaland urodynamic results after five injections in patients withneurogenic detrusor overactivity. Eur Urol. 2007 Dec;52(6):1729

Reitz A, Schurch B., Botulinum toxin type B injection formanagement of type A resistant neurogenic detrusor overactivity.J Urol. 2004 Feb;171(2 Pt 1):804

Reitz A, Stöhrer M, Kramer G et al. European experience of 200cases treated with botulinum-A toxin injections into the detrusormuscle for urinary incontinence due to neurogenic detrusoroveractivity. Eur Urol. 2004 Apr;45(4):510

Rembratt A, Norgaard JP, Andersson KE. Desmopressin in elderlypatients with nocturia: short-term safety and effects on urineoutput, sleep and voiding patterns. BJU. Int. 2003;91(7), 642

Rembratt A, Riis A, Norgaard JP. Desmopressin treatment innocturia; an analysis of risk factors for hyponatremia. NeurourolUrodyn 2006;25(2):105

Riccabona M. Pediatric MRU--its potential and its role in thediagnostic work-up of upper urinary tract dilatation in infants andchildrenWorld J Urol. 2004 Jun;22(2):79

Rios LA, Panhoca R, Mattos D Jr et al. Intravesical resiniferatoxinfor the treatment of women with idiopathic detrusor overactivityand urgency incontinence: A single dose, 4 weeks, double-blind,randomized, placebo controlled trial. Neurourol Urodyn2007;26(6):773

Robinson D, Cardozo L. The role of estrogens in female lowerurinary tract dysfunction. Urology 2003;62(4 Suppl 1):45

Robinson D, Cardozo L, Akeson M et al. Antidiuresis: a newconcept in managing female daytime urinary incontinence. BJUInt 2004;93:996

Robinson D, Cardozo L, Terpstra G et al. A randomized double-

blind placebo-controlled multicentre study to explore the efficacyand safety of tamsulosin and tolterodine in women with overactivebladder syndrome. BJU Int. 2007 Oct;100(4):840

Robinson D, Rainer RO, Washburn SA et al. Effects of estrogenand progestin replacement on the urogenital tract of theovariectomized cynomolgus monkey. Neurourol Urodyn1996;15(3):215

Roe CM, Anderson MJ, Spivack B. Use of anticholinergicmedications by older adults with dementia. J Am Geriatr Soc2002;50:836

Roehrborn CG, Kaplan SA, Jones JS et al. Tolterodine extendedrelease with or without tamsulosin in men with lower urinary tractsymptoms including overactive bladder symptoms: effects ofprostate size. Eur Urol. 2008 Jun 17. [Epub ahead of print]

Rogers R, Bachmann G, Jumadilova Z et al. Efficacy of tolterodineon overactive bladder symptoms and sexual and emotional qualityof life in sexually active women. Int Urogynecol J Pelvic FloorDysfunct. 2008 Nov;19(11):1551

Rovner ES, Kreder K, Sussman DO et al. Effect of tolterodineextended release with or without tamsulosin on measures ofurgency and patient reported outcomes in men with lower urinarytract symptoms. J Urol. 2008 Sep;180(3):1034

Rovner ES, Rackley R, Nitti VW et al. Tolterodine extendedrelease is efficacious in continent and incontinent subjects withoveractive bladder. Urology. 2008 sept;72(3):488

Rudy D, Cline K, Harris R et al. Multicenter phase III trial studyingtrospium chloride in patients with overactive bladder. Urology2006 Feb;67(2):275

Rufford J, Hextall A, Cardozo L et al. A double blind placebocontrolled trial on the effects of 25 mg estradiol implants on theurge syndrome in postmenopausal women. Int Urogynecol JPelvic Floor Dysfunct 2003;14(2):78

Ruffmann R. A review of flavoxate hydrochloride in the treatmentof urge incontinence. J Int Med Res 1988;16:317

Ruggieri MR Sr. Mechanisms of disease: role of purinergicsignaling in the pathophysiology of bladder dysfunction. Nat ClinPract Urol. 2006 Apr;3(4):206

Ruggieri MR Sr, Braverman AS, Pontari MA. Combined use ofalpha-adrenergic and muscarinic antagonists for the treatmentof voiding dysfunction. J Urol. 2005 Nov;174(5):1743

Sadananda P, Chess-Williams R, Burcher E. Contractile propertiesof the pig bladder mucosa in response to neurokinin A: a role formyofibroblasts? Br J Pharmacol 2008; 153:1465

Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol inthe treatment of idiopathic detrusor overactivity: a double-blind,placebo-controlled, randomized study. Br J Clin Pharmacol. 2006Apr;61(4):456

Saffroy M, Torrens Y, Glowinski J et al. Autoradiographic distributionof tachykinin NK2 binding sites in the rat brain: comparison withNK1 and NK3 binding sites. Neuroscience. 2003;116(3):761

Sahai A, Khan MS, Dasgupta P, Efficacy of botulinum toxin-A fortreating idiopathic detrusor overactivity: results from a singlecenter, randomized, double-blind, placebo controlled trial J Urol.2007 Jun;177(6):2231

Sahai A, Mallina R, Dowson C et al. Evolution of transdermaloxybutynin in the treatment of overactive bladder. Int J Clin Pract.2008 Jan;62(1):167

Sairam K, Kulinskaya E, McNicholas TA et al. Sildenafil influenceslower urinary tract symptoms. BJU Int. 2002 Dec;90(9):836

Salvatore S, Serati M, Cardozo L et al. Cognitive dysfunctionwith tolterodine use. Am J Obstet Gynecol 2007;197:e8.

Salvatore S, Serati M, Bolis P. Tolterodine for the treatment ofoveractive bladder. Expert Opin Pharmacother. 2008May;9(7):1249

Schagen van Leeuwen JH, Lange RR, Jonasson AF et al. Efficacy

696

and safety of duloxetine in elderly women with stress urinaryincontinence or stress-predominant mixed urinary incontinence.Maturitas. 2008 Jun 20;60(2):138

Schmid DMS, Roy-Guggenbuehl SG, Werner MW et al. TheZurich experiences including 6 year results of 200 cases treatedwith Botulinum-A toxin injections into the detrusor muscle foroveractive bladder refractory to anticholinergics. Eur Urol Suppl,2008:7(3):212.

Schmid DM, Sauermann P, Werner M et al. Experience with 100cases treated with botulinum-A toxin injections in the detrusormuscle for idiopathic overactive bladder syndrome refractory toanticholinergics. J Urol. 2006 Jul;176(1):177

Schneider T, Fetscher C, Krege S et al. Signal transductionunderlying carbachol-induced contraction of human urinarybladder. J Pharmacol Exp Ther 2004; 309:1148

Schneider T, Hein P, Bai J et al. A role for muscarinic receptorsor rho-kinase in hypertension associated rat bladder dysfunction?J Urol 2005b;173:2178

Schneider T, Hein P, Michel MC. Signal transduction underlyingcarbachol-induced contraction of rat urinary bladder. I.Phospholipases and Ca2+ sources. J Pharmacol Exp Ther 2004;308:47

Schneider T, Hein P, Michel-Reher M et al. Effects of ageing onmuscarinic receptor subtypes and function in rat urinary bladder.Naunyn-Schmiedeberg's Arch Pharmacol 2005a;372:71

Schröder A, Colli E, Maggi M et al. Effects of a vitamin D3analogue in a rat model of bladder outflow obstruction. BJU Int2006; 98:637

Schroeder FH, Westerhof M, Bosch RJLH, Kurth KH. Benignprostatic hyperplasia treated by castration or the LH-RH analoguebuserelin: a report on 6 cases. Eur Urol 1986;12:318

Schulte-Baukloh H, Knispel HH, Stolze T et al. Repeatedbotulinum-A toxin injections in treatment of children with neurogenicdetrusor overactivity. Urology. 2005 Oct;66(4):865

Schulte-Baukloh H, Michael T, Schobert J et al. Efficacy ofbotulinum-a toxin in children with detrusor hyperreflexia due tomyelomeningocele: preliminary results, J Urol 2003 Jun;169(6):2430.

Schulte-Baukloh H, Mürtz G, Henne T et al. Urodynamic effectsof propiverine hydrochloride in children with neurogenic detrusoroveractivity: a prospective analysis. BJU Int. 2006 Feb;97(2):355

Schulte-Baukloh H, Zurawski TH, Knispel HH et al. Persistenceof the synaptosomal-associated protein-25 cleavage productafter intradetrusor botulinum toxin A injections in patients withmyelomeningocele showing an inadequate response to treatment.BJU Int. 2007 Nov;100(5):1075

Schurch B, Denys P, Kozma CM et al. Botulinum toxin A improvesthe quality of life of patients with neurogenic urinary incontinence.Eur Urol. 2007 Sep;52(3):850

Schurch B, de Sèze M, Denys P et al. Botulinum toxin type a isa safe and effective treatment for neurogenic urinary incontinence:results of a single treatment, randomized, placebo controlled 6-month study. J Urol. 2005 Jul;174(1):196

Schurch B, Schmid DM, Stöhrer M. Treatment of neurogenicincontinence with botulinum toxin A. N Engl J Med. 2000a Mar2;342(9):665

Schurch B, Stöhrer M, Kramer G et al. Botulinum-A toxin fortreating detrusor hyperreflexia in spinal cord injured patients: anew alternative to anticholinergic drugs? Preliminary results. J Urol.2000b Sep;164(3 Pt 1):692

Seki S, Erickson KA, Seki M et al. Elimination of rat spinal neuronsexpressing neurokinin 1 receptors reduces bladder overactivityand spinal c-fos expression induced by bladder irritation. Am JPhysiol Renal Physiol. 2005 Mar;288(3):F466

Serra DB, Affrime MB, Bedigian MP et al. QT and QTc intervalwith standard and supratherapeutic doses of darifenacin, a

muscarinic M3 selective receptor antagonist for the treatment ofoveractive bladder. J Clin Pharmacol. 2005 Sep;45(9):1038

Shamliyan TA, Kane RL, Wyman J et al. Systematic review:randomized, controlled trials of nonsurgical treatments for urinaryincontinence in women. Ann Int Med 2008;148:459

Sharma A, Goldberg MJ, Cerimele BJ: Pharmacokinetics andsafety of duloxetine, a dual- serotonin and norepinephrine reuptakeinhibitor. J Clin Pharmacol 2000;40(2):161

Sheldon JH, Norton NW, Argentieri TM. Inhibition of guinea pigdetrusor contraction by NS-1619 is associated with activation ofBKCa and inhibition of calcium currents. J Pharmacol Exp Ther1997; 283: 1193

Sheu MT, Yeh GC, Ke WT et al. Development of a high-performance liquid chromatographic method for bioequivalencestudy of flavoxate tablets. J Chromatogr B Biomed Sci Appl2001;751(1):79

Shieh C-C, Brune ME, Buckner SA, et al. Characterization of anovel ATP-sensitive K+ channel opener, A-251179, on urinarybladder relaxation and cystometric parameters. Br J Pharmacol2007; 151: 467

Shieh C-C, Feng L, Buckner SA, et al. Functional implications ofspare ATP-sensitive K+ channels in bladder smooth muscle cells.J Pharmacol Exp Ther 2001; 296: 669

Siddiqui MA, Perry CM, Scott LJ. Oxybutynin extended- release:a review of its use in the management of overactive bladder.Drugs, 2004;64(8):885

Silva C, Ribeiro MJ, Cruz F. The effect of intravesical resiniferatoxinin patients with idiopathic detrusor instability suggests thatinvoluntary detrusor contractions are triggered by C-fiber input.J Urol. 2002 Aug;168(2):575

Silva C, Rio ME, Cruz F, Desensitization of bladder sensory fibersby intravesical resiniferatoxin, a capsaicin analog: long-termresults for the treatment of detrusor hyperreflexia. Eur Urol. 2000Oct;38(4):444

Silva C, Silva J, Castro H et al. Bladder sensory desensitizationdecreases urinary urgency. BMC Urol. 2007 Jun;11(7):9

Silva C, Silva J, Ribeiro MJ et al. Urodynamic effect of intravesicalresiniferatoxin in patients with neurogenic detrusor overactivityof spinal origin: results of a double-blind randomized placebo-controlled trial. Eur Urol. 2005 Oct; 48 (4):650

Singh SK, Agarwal MM, Batra YK, Kishore AV, Mandal AK. Effectof lumbar-epidural administration of tramadol on lower urinary tractfunction. Neurourol Urodyn. 2008;27(1):65

Sjögren C, Andersson K-E, Husted S et al. Atropine resistanceof the transmurally stimulated isolated human bladder. J Urol1982;128:1368

Skerjanec A. The clinical pharmacokinetics of darifenacin. ClinPharmacokinet. 2006;45(4):325

Smet PJ, Moore KH, Jonavicius J. Distribution and colocalizationof calcitonin gene-related peptide, tachykinins, and vasoactiveintestinal peptide in normal and idiopathic unstable human urinarybladder. Lab Invest. 1997 Jul;77(1):37

Smith PH, Cook JB, Prasad EW.The effect of ubretid on bladderfunction after recent complete spinal cord injury. Br J Urol. 1974Apr;46(2):187

Smith CP, Gangitano DA, Munoz A et al. Botulinum toxin type Anormalizes alterations in urothelial ATP and NO release inducedby chronic spinal cord injury. Neurochem Int. 2008 May;52(6):1068

Smith N, Grimes I, Ridge S et al. YM905 is effective and safe astreatment of overactive bladder in women and men: Results fromphase II study. ICS Proceedings. Heidelberg, Germany: 138(abstract 222), 2002

Smith P, Heimer G, Norgren A et al. Steroid hormone receptorsin pelvic muscles and ligaments in women. Gynecol ObstetInvestig 1990;30(1):27

697

Smulders RA, Krauwinkel WJ, Swart PJ et al. Pharmacokineticsand safety of solifenacin succinate in healthy young men. J ClinPharmacol. 2004 Sep;44(9):1023

Smulders R, Tan H, Krauwinkel W et al. A placebo-controlled, dose–rising study in healthy male volunteers to evaluate safety,tolerability, pharmacokinetics and pharmacodynamics of singleoral doses of YM905. Presented at the 32nd InternationalContinence Society Annual Meeting, Heidelberg, Germany, August2002

Song C, Park JT, Heo KO et al. Effects of bladder training and/ortolterodine in female patients with overactive bladder syndrome:a prospective, randomized study. J Korean Med Sci. 2006Dec;21(6):1060

Sperling R, Greve D, Dale A et al. Functional MRI detection ofpharmacologically induced memory impairment. Proc Natl AcadSci USA 2002;99:455

Stahl MM, Ekstrom B, Sparf B et al. Urodynamic and other effectsof tolterodine: a novel antimuscarinic drug for the treatment ofdetrusor overactivity. Neurourol Urodyn, 1995;14(6):647

Stanton SL. A comparison of emepronium bromide and flavoxatehydrochloride in the treatment of urinary incontinence. J Urol1973;110:529

Starr JM. Cholinesterase inhibitor treatment and urinaryincontinence in Alzheimer’s disease. J Am Geriatr Soc 2007;55:800

Staskin D, Sand P, Zinner N et al. Trospium Study Group. Oncedaily trospium chloride is effective and well tolerated for thetreatment of overactive bladder: results from a multicenter phaseIII trial. J Urol 2007 Sep;178(3 Pt 1):978

Staskin DR, Te AE. Short- and long-term efficacy of solifenacintreatment in patients with symptoms of mixed urinary incontinence.BJU Int. 2006 Jun;97(6):1256

Steers W, Corcos J, Foote J et al. An investigation of dose titrationwith darifenacin, an M3-selective receptor antagonist. BJU Int.2005 Mar;95(4):580

Steers WD, Herschorn S, Kreder KJ et al. Duloxetine comparedwith placebo for treating women with symptoms of overactivebladder. BJU Int. 2007 Aug;100(2):337

Stengel PW, Yamada M, Wess J et al. M3-receptor knockoutmice: muscarinic receptor function in atria, stomach fundus,urinary bladder, and trachea. Am J Physiol Regul Integr CompPhysiol 2002; 282: R1443

Stevens LA, Chapple CR, Chess-Williams R. Human idiopathicand neurogenic overactive bladders and the role of M2 muscarinicreceptors in contraction. Eur Urol. 2007 Aug;52(2):531-8.

Stewart DA, Taylor J, Ghosh S et al. Terodiline causes polymorphicventricular tachycardia due to reduced heart rate and prolongationof QT interval. Eur J Clin Pharmacol. 1992;42(6):577

Stief CG, Porst H, Neuser D et al. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafilin the treatment of lower urinary tract symptoms secondary tobenign prostatic hyperplasia. Eur Urol. 2008 Jun;53(6):1236

Stöhrer M, Bauer P, Giannetti BM et al. Effect of trospium chlorideon urodynamic parameters in patients with detrusor hyperreflexiadue to spinal cord injuries: a multicentre placebo controlleddouble-blind trial. Urol Int 1991;47:138

Stöhrer, M., Madersbacher, H., Richter, R. et al. Efficacy andsafety of propiverine in SCI-patients suffering from detrusorhyperreflexia—a double-blind, placebo-controlled clinical trial.Spinal Cord 1999:37:196

Stöhrer M, Mürtz G, Kramer G et al. Propiverine compared tooxybutynin in neurogenic detrusor overactivity--results of arandomized, double-blind, multicenter clinical study. Eur Urol.2007 Jan;51(1):235

Streng T, Christoph T, Andersson K-E. Urodynamic effects of theK+ channel (KCNQ) opener retigabine in freely moving, consciousrats. J Urol 2004; 172: 2054

Striano P, Striano S. Gabapentin: a Ca2+ channel alpha 2-deltaligand far beyond epilepsy therapy. Drugs Today (Barc). 2008May;44(5):353

Sugiyama Y, Yoshida M, Masunaga K et al. Pharmacologicaleffects of propiverine and its active metabolite, M-1, on isolatedhuman urinary bladder smooth muscle, and on bladder contractionin rats. Int J Urol. 2008 Jan;15(1):76

Sultana CJ, Walters MD. Estrogen and urinary incontinence inwomen. Maturitas 1990;20:129

Sussman D, Garely A. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: theantimuscarinic clinical effectiveness trial (ACET). Curr Med ResOpin 2002;18 (4):177

Swart PJ, Krauwinkel WJ, Smulders RA et al. Pharmacokineticeffect of ketoconazole on solifenacin in healthy volunteers. BasicClin Pharmacol Toxicol. 2006 Jul;99(1):33.

Szallasi A, Cruz F, Geppetti P. TRPV1: a therapeutic target fornovel analgesic drugs?. Trends Mol Med. 2006 Nov;12(11):545

Szonyi G, Collas DM, Ding YY et al. Oxybutynin with bladderretraining for detrusor instability in elderly people: a randomizedcontrolled trial. Age Aging, 1995;24:287

Szollar SM, Lee SM. Intravesical oxybutynin for spinal cord injurypatients. Spinal Cord, 1996;34:284

Tadic SD, Griffiths D, Schaefer W et al. Abnormal connectionsin the supraspinal bladder control network in women with urgeurinary incontinence. Neuroimage 2008 Feb 15;39(4):1647-53.

Takasu T, Ukai M, Sato S et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide(YM178), a novel selective beta3-adrenoceptor agonist, on bladderfunction. J Pharmacol Exp Ther. 2007 May;321(2):642

Takeda M, Obara K, Mizusawa T et al. Evidence for beta3-adrenoceptor subtypes in relaxation of the human urinary bladderdetrusor: analysis by molecular biological and pharmacologicalmethods. J Pharmacol Exp Ther. 1999 Mar;288(3):1367

Takeda H, Yamazaki Y, Igawa Y et al. Effects of beta(3)-adrenoceptor stimulation on prostaglandin E(2)-induced bladderhyperactivity and on the cardiovascular system in conscious rats.Neurourol Urodyn. 2002;21(6):558

Tanaka M, Sasaki Y, Kimura Y et al. A novel pyrrole derivative,NS-8, suppresses the rat micturition reflex by inhibiting afferentpelvic nerve activity. BJU Int 2003; 92: 1031

Taylor MC, Bates CP, A double-blind crossover trial of baclofen--a new treatment for the unstable bladder syndrome. Br J Urol.1979 Dec;51(6):504

The Montreal Cognitive Assessment homepage. Accessed athttp://www.mocatest.org on June 4, 2008

Thor K, Katofiasc MA. Effects of duloxetine, a combined serotoninand norepinephrine reuptake inhibitor, on central neural controlof lower urinary tract function in the chloralose-anesthetizedfemale cat. J Pharmacol Exp Ther 1995;274(2):1014

Thüroff JW, Bunke B, Ebner A et al. Randomized, double-blind,multicenter trial on treatment of frequency, urgency andincontinence related to detrusor hyperactivity: oxybutynin versuspropantheline vesus placebo. J Urol, 1991;145:813

Todorova A, Vonderheid-Guth B, Dimpfel W. Effects of tolterodine,trospium chloride, and oxybutynin on the central nervous system.J Clin Pharmacol 2001;41(6):636

Tokuno H, Chowdhury JU, Tomita T. Inhibitory effects of propiverineon rat and guinea-pig urinary bladder muscle. Naunyn-Schmiedeberg´s Arch Pharmacol, 1993;348:659

Truss MC, Stief CG, Uckert S et al. Initial clinical experience withthe selective phosphodiesterase-I isoenzyme inhibitor vinpocetinein the treatment of urge incontinence and low compliance bladder.World J Urol 2000;18:439

Truss MC, Stief CG, Uckert S et al. Phosphodiesterase 1 inhibition

698

in the treatment of lower urinary tract dysfunction: from bench tobedside. World J Urol 2001;19:344

Tsakiris P, de la Rosette JJ, Michel M et al. Pharmacologictreatment of male stress urinary incontinence: systemic reviewof the literature and levels of evidence. European Urology2008;53:53-59

Tsao JW, Heilman KM. Transient memory impairment andhallucinations associated with tolterodine use. N Engl J Med2003;349:2274

Uchida H, Shishido K, Nomiya M et al. Involvement of cyclicAMP-dependent and -independent mechanisms in the relaxationof rat detrusor muscle via beta-adrenoceptors.

Eur J Pharmacol. 2005 Aug 22;518(2-3):195

Uckert S, Kuthe A, Jonas U et al. Characterization and functionalrelevance of cyclic nucleotide phosphodiesterase isoenzymesof the human prostate. J Urol 2001;166:2484

Uckert S, Stief CG, Odenthal KP et al. Responses of isolatednormal human detrusor muscle to various spasmolytic drugscommonly used in the treatment of the overactive bladder.Arzneimittelforschung, 2000;50(5):456

Valiquette G, Herbert J, Maede-D'Alisera P. Desmopressin in themanagement of nocturia in patients with multiple sclerosis. Adouble-blind, crossover trial. Arch Neurol 1996;53:1270

Vande Walle JGJ, Bogaert GA, Mattsson S et al. A new fast-melting oral formulation of desmopressin: a pharmacodynamicstudy in children with primary nocturnal enuresis. BJU Int2006;97:603

Van Kerrebroeck P, Abrams P, Lange R et al. Duloxetine vs.placebo in the treatment of European and Canadian women withstress urinary incontinence. Br J Obstet Gynaecol 2004;111:249

Van Kerrebroeck P, Kreder K, Jonas U et al. Tolterodine once-daily: superior efficacy and tolerability in the treatment of theoveractive bladder. Urology, 2001;57(3):414

van Kerrebroeck P, Rezapour M, Cortesse A et al. Desmopressinin the treatment of nocturia: a double-blind, placebo-controlledstudy. Eur Urol 2007;52:221

Versi E, Appell R, Mobley D et al. Dry mouth with conventionaland controlled-release oxybutynin in urinary incontinence. TheDitropan XL Study Group. Obstet Gynecol, 2000;95(5):718-721

Versi E, Cardozo LD. Urethral instability: diagnosis based onvariations in the maximum urethral pressure in normal climactericwomen. Neurourol Urodynamics 1986;5(6):535

Waetjen LE, Brown JS, Modelska K et al. Effect of raloxifene onurinary incontinence: a randomized controlled trial. ObstetGynaecol 2004;103(2)261

Wagg A, Wyndaele JJ, Sieber P. Efficacy and tolerability ofsolifenacin in elderly subjects with overactive bladder syndrome:a pooled analysis. Am J Geriatr Pharmacother. 2006 Mar;4(1):14

Waldeck K, Larsson B, Andersson K-E. Comparison of oxybutyninand its active metabolite, N-desethyl-oxybutynin, in the humandetrusor and parotid gland. J Urol, 1997;157:1093

Walter P, Grosse J, Bihr AM et al. Bioavailability of trospiumchloride after intravesical instillation in patients with neurogeniclower urinary tract dysfunction: A pilot study. Neurourol Urodyn.1999;18(5):447-53.

Walter R, Ullmann C, Thummler et al. Influence of propiverineon hepatic microsomal cytochrome p450 enzymes in male rats.Drug Metab Dispos 2003;31(6):714

Wammack R, Weihe, E., Dienes, H.-P., and Hohenfellner, R. DieNeurogene Blase in vitro. Akt Urol, 1995;26:16

Weatherall M. The risk of hyponatremia in older adults usingdesmopressin for nocturia: a systematic review and meta-analysis.Neurourol Urodyn 2004;23(4):302

Wegener JW, Schulla V, Lee T-S, et al. An essential role ofCaV1.2 L-type calcium channel for urinary bladder function.FASEB J 2004; 18: 1159

Weil EH, Eerdmans PH, Dijkman GA et al. Randomized double-blind placebo controlled multicenter evaluation of efficacy and dosefinding of midodrine hydrochloride in women with mild to moderatestress urinary incontinence: a phase II study. Int Urogynecol JPelvic Floor Dysfunct 1998;9(3):145

Wein AJ. Pathophysiology and Categorization of VoidingDysfunction. In, Walsh, P., Retik, A., Vaughan, E.D., Jr., Wein, A.J.(eds): Campbells Urology, Eighth Edition, Saunders, Philadelphia,pp. 887-898, 2002

Wegener JW, Schulla V, Lee T-S, et al. An essential role ofCaV1.2 L-type calcium channel for urinary bladder function.FASEB J 2004; 18: 1159

Wehnert J, Sage S. Comparative investigations to the action ofMictonorm (propiverin hydrochloride) and Spasuret (flavoxathydrochloride) on detrusor vesicae. Z Urol Nephrol, 1989;82:259

Wehnert J, Sage S. Therapie der Blaseninstabilität und Urge-Inkontinenz mit Propiverin hydrochlorid (Mictonorm®) undOxybutynin chlorid (Dridase®) - eine randomisierte Crossover-Vergleichsstudie. Akt Urol, 1992;23:7

Werkström V, Persson K, Ny L et al. Factors involved in therelaxation of female pig urethra evoked by electrical fieldstimulation. Br J Pharmacol 1995;116:1599

Werkström V, Svensson A, Andersson KE et al. Phosphodiesterase5 in the female pig and human urethra: morphological andfunctional aspects. BJU Int. 2006 Aug;98(2):414

Wiedemann A, Füsgen I, Hauri D. New aspects of therapy withtrospium chloride for urge incontinence. Eur J Geriatrics 2002;3:41

Williams SG, Staudenmeier J. Hallucinations with tolterodine.Psychiatr Serv 2004;55:1318

Womack KB, Heilman KM. Tolterodine and memory: dry butforgetful. Arch Neurol 2003;60:771

Woods M, Carson N, Norton NW et al. Efficacy of the beta3-adrenergic receptor agonist CL-316243 on experimental bladderhyperreflexia and detrusor instability in the rat. J Urol. 2001Sep;166(3):1142

Wuest M, Hiller N, Braeter M et al. Contribution of Ca2+ influx tocarbachol-induced detrusor contraction is different in humanurinary bladder compared to pig and mouse. Eur J Pharmacol2007; 565: 180

Wuest M, Kaden S, Hakenberg OW et al. Effect of rilmakalim ondetrusor contraction in the presence and absence of urothelium.Naunyn-Schmiedeberg's Arch Pharmacol 2005; 372:203.

Wuest M, Weiss A, Waelbroeck M et al. Propiverine andmetabolites: differences in binding to muscarinic receptors andin functional models of detrusor contraction. NaunynSchmiedebergs Arch Pharmacol. 2006 Nov;374(2):87

Wyndaele JJ, Van Dromme SA, Muscular weakness as sideeffect of botulinum toxin injection for neurogenic detrusoroveractivity. Spinal Cord. 2002 Nov;40(11):599

Yamaguchi O, Marui E, Kakizaki H et al. Randomized, double-blind, placebo- and propiverine-controlled trial of the once-dailyantimuscarinic agent solifenacin in Japanese patients withoveractive bladder. BJU Int. 2007 Sep;100(3):579

Yarker YE, Goa KL, Fitton A. Oxybutynin - A review of itspharmacodynamic and pharmacokinetic properties, and itstherapeutic use in detrusor instability. Drugs Aging, 1995;6:243

Yaminishi T, Yasuda K, Tojo M et al. Effects of beta-2 stimulantson contractility and fatigue of canine urethral sphincter. J Urol1994;151:1073

Yasuda K, Kawabe K, Takimoto Y et al. A double blind clinical trialof a beta-2 adrenergic agonist in stress incontinence. Int.Urogynecol J, 1993;4:146

Yoshida M, Homma Y, Inadome A et al. Age-related changes incholinergic and purinergic neurotransmission in human isolatedbladder smooth muscles. Exp Gerontol 2001;36(1):99

699

Yoshida M, Inadome A, Maeda Y et al. Non-neuronal cholinergicsystem in human bladder urothelium. Urology. 2006 Feb;67(2):425

Yoshida M, Masunaga K, Satoji Y et al. Basic and clinical aspectsof non-neuronal acetylcholine: expression of non-neuronalacetylcholine in urothelium and its clinical significance. J PharmacolSci. 2008 Feb;106(2):193

Yoshida M, Miyamae K, Iwashita H et al. Management of detrusordysfunction in the elderly: changes in acetylcholine and adenosinetriphosphate release during aging. Urology. 2004 Mar;63(3 Suppl1):17

Yossepowitch O, Gillon G, Baniel J et al. The effect of cholinergicenhancement during filling cystometry: can edrophonium chloridebe used as a provocative test for overactive bladder? J Urol.2001 May;165(5):1441

Zahariou A, Karagiannis G, Papaionnou P et al. The use ofdesmopressin in the management of nocturnal enuresis in patientswith spinal cord injury. Eura Medicophys 2007;43:333

Zarghooni S, Wunsch J, Bodenbenner M et al. Expression ofmuscarinic and nicotinic acetylcholine receptors in the mouseurothelium. Life Sci 2007;80:2308

Zhu HL, Brain KL, Aishima M et al. Actions of two main metabolitesof propiverine (M-1 and M-2) on voltage-dependent L-type Ca2+currents and Ca2+ transients in murine urinary bladder myocytes.J Pharmacol Exp Ther. 2008 Jan;324(1):118

Zinner N, Gittelman M, Harris R et al. Trospium StudyGroup.Trospium chloride improves overactive bladder symptoms:a multicenter phase III trial. J Urol 2004a;171(6 Pt 1):2311

Zinner NR, Mattiasson A, Stanton SL. Efficacy, safety, andtolerability of extended-release once-daily tolterodine treatmentfor overactive bladder in older versus younger patients. J AmGeriatr Soc 1002;50(5):799

Zinner N, Susset J, Gittelman M et al. Efficacy, tolerability andsafety of darifenacin, an M(3) selective receptor antagonist: aninvestigation of warning time in patients with OAB. Int J ClinPract. 2006 Jan;60(1):119

700